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Siedlecka-Kroplewska K, Kmiec Z, Zmijewski MA. The Interplay Between Autophagy and Apoptosis in the Mechanisms of Action of Stilbenes in Cancer Cells. Antioxidants (Basel) 2025; 14:339. [PMID: 40227400 PMCID: PMC11939748 DOI: 10.3390/antiox14030339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 04/15/2025] Open
Abstract
Plant-based stilbenes are low-molecular-weight polyphenolic compounds that exhibit anti-oxidant, anti-microbial, anti-fungal, anti-inflammatory, anti-diabetic, cardioprotective, neuroprotective, and anti-cancer activities. They are phytoalexins produced in diverse plant species in response to stress, such as fungal and bacterial infections or excessive UV irradiation. Plant-derived dietary products containing stilbenes are common components of the human diet. Stilbenes appear to be promising chemopreventive and chemotherapeutic agents. Accumulating evidence indicates that stilbenes are able to trigger both apoptotic and autophagic molecular pathways in many human cancer cell lines. Of note, the molecular crosstalk between autophagy and apoptosis under cellular stress conditions determines the cell fate. The autophagy and apoptosis relationship is complex and depends on the cellular context, e.g., cell type and cellular stress level. Apoptosis is a type of regulated cell death, whereas autophagy may act as a pro-survival or pro-death mechanism depending on the context. The interplay between autophagy and apoptosis may have an important impact on chemotherapy efficiency. This review focuses on the in vitro effects of stilbenes in different human cancer cell lines concerning the interplay between autophagy and apoptosis.
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Affiliation(s)
| | - Zbigniew Kmiec
- Department of Anatomy and Histology, School of Medicine, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland;
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Cabrera-Serrano AJ, Sánchez-Maldonado JM, González-Olmedo C, Carretero-Fernández M, Díaz-Beltrán L, Gutiérrez-Bautista JF, García-Verdejo FJ, Gálvez-Montosa F, López-López JA, García-Martín P, Pérez EM, Sánchez-Rovira P, Reyes-Zurita FJ, Sainz J. Crosstalk Between Autophagy and Oxidative Stress in Hematological Malignancies: Mechanisms, Implications, and Therapeutic Potential. Antioxidants (Basel) 2025; 14:264. [PMID: 40227235 PMCID: PMC11939785 DOI: 10.3390/antiox14030264] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 04/15/2025] Open
Abstract
Autophagy is a fundamental cellular process that maintains homeostasis by degrading damaged components and regulating stress responses. It plays a crucial role in cancer biology, including tumor progression, metastasis, and therapeutic resistance. Oxidative stress, similarly, is key to maintaining cellular balance by regulating oxidants and antioxidants, with its disruption leading to molecular damage. The interplay between autophagy and oxidative stress is particularly significant, as reactive oxygen species (ROS) act as both inducers and by-products of autophagy. While autophagy can function as a tumor suppressor in early cancer stages, it often shifts to a pro-tumorigenic role in advanced disease, aiding cancer cell survival under adverse conditions such as hypoxia and nutrient deprivation. This dual role is mediated by several signaling pathways, including PI3K/AKT/mTOR, AMPK, and HIF-1α, which coordinate the balance between autophagic activity and ROS production. In this review, we explore the mechanisms by which autophagy and oxidative stress interact across different hematological malignancies. We discuss how oxidative stress triggers autophagy, creating a feedback loop that promotes tumor survival, and how autophagic dysregulation leads to increased ROS accumulation, exacerbating tumorigenesis. We also examine the therapeutic implications of targeting the autophagy-oxidative stress axis in cancer. Current strategies involve modulating autophagy through specific inhibitors, enhancing ROS levels with pro-oxidant compounds, and combining these approaches with conventional therapies to overcome drug resistance. Understanding the complex relationship between autophagy and oxidative stress provides critical insights into novel therapeutic strategies aimed at improving cancer treatment outcomes.
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Affiliation(s)
- Antonio José Cabrera-Serrano
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
| | - José Manuel Sánchez-Maldonado
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18012 Granada, Spain
| | - Carmen González-Olmedo
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - María Carretero-Fernández
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
| | - Leticia Díaz-Beltrán
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Juan Francisco Gutiérrez-Bautista
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Servicio de Análisis Clínicos e Inmunología, University Hospital Virgen de las Nieves, 18014 Granada, Spain
- Department of Biochemistry, Molecular Biology and Immunology III, University of Granada, 18016 Granada, Spain
| | - Francisco José García-Verdejo
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Fernando Gálvez-Montosa
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - José Antonio López-López
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Paloma García-Martín
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Campus de la Salud Hospital, PTS, 18016 Granada, Spain
| | - Eva María Pérez
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Campus de la Salud Hospital, PTS, 18016 Granada, Spain
| | - Pedro Sánchez-Rovira
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Fernando Jesús Reyes-Zurita
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18012 Granada, Spain
| | - Juan Sainz
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18012 Granada, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
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Tripathi A, Chauhan S, Khasa R. A Comprehensive Review of the Development and Therapeutic Use of Antivirals in Flavivirus Infection. Viruses 2025; 17:74. [PMID: 39861863 PMCID: PMC11769230 DOI: 10.3390/v17010074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/27/2025] Open
Abstract
Flaviviruses are a diverse group of viruses primarily transmitted through hematophagous insects like mosquitoes and ticks. Significant expansion in the geographic range, prevalence, and vectors of flavivirus over the last 50 years has led to a dramatic increase in infections that can manifest as hemorrhagic fever or encephalitis, leading to prolonged morbidity and mortality. Millions of infections every year pose a serious threat to worldwide public health, encouraging scientists to develop a better understanding of the pathophysiology and immune evasion mechanisms of these viruses for vaccine development and antiviral therapy. Extensive research has been conducted in developing effective antivirals for flavivirus. Various approaches have been extensively utilized in clinical trials for antiviral development, targeting virus entry, replication, polyprotein synthesis and processing, and egress pathways exploiting virus as well as host proteins. However, to date, no licensed antiviral drug exists to treat the diseases caused by these viruses. Understanding the mechanisms of host-pathogen interaction, host immunity, viral immune evasion, and disease pathogenesis is highly warranted to foster the development of antivirals. This review provides an extensively detailed summary of the most recent advances in the development of antiviral drugs to combat diseases.
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Affiliation(s)
- Aarti Tripathi
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA;
- Galveston National Laboratory, Galveston, TX 77555, USA
| | - Shailendra Chauhan
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA;
- Galveston National Laboratory, Galveston, TX 77555, USA
| | - Renu Khasa
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami/UHealth, Miami, FL 33136, USA
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Zhang J, Chen S, Zhang R, Zheng X, Liu C, Zhang J, Zhang L, Yang Z, Wang L. Rapamycin ameliorates inflammatory pain via recovery of autophagy flux mediated by mammalian target of rapamycin (mTOR) signaling pathway in the rat spinal cord. Int J Immunopathol Pharmacol 2025; 39:3946320251317284. [PMID: 39895094 PMCID: PMC11789103 DOI: 10.1177/03946320251317284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 01/16/2025] [Indexed: 02/04/2025] Open
Abstract
OBJECTIVE This study aimed to investigate the effect of rapamycin on inflammatory pain in rats. INTRODUCTION Inflammatory pain is a kind of pathological pain caused by inflammatory mediators or factors such as TNF-α (Tumor Necrosis Factor-α), IL-1β (Interleukin-1β), and IL-6 (Interleukin-6). NSAIDs and opioid analgesics are commonly used for relieving inflammatory pain, but the side effects limit their clinical application. New drugs based on new mechanisms for inflammatory pain are urgently needed. Autophagy is an evolutionarily conserved homeostatic process for lysosomal degradation of intracellular components. Recent reports indicate the involvement of autophagy in the development and maintenance of neuropathic pain, but the role of autophagy in inflammatory pain still needs to be explored. METHODS The pain-related behaviors of rats were studied by paw withdrawal threshold and paw withdrawal latency. The autophagy level of the rat spinal cord was detected by western blots. The concentrations of TNF-α, IL-1β, and IL-6 were detected by ELISA. RESULTS We found that the paw withdrawal threshold and paw withdrawal latency were both significantly decreased after CFA (Complete Freund's Adjuvant) injection, accompanied by the activation of mTOR signaling pathway and the inhibited autophagy flux in the spinal cord. And inflammatory cytokines were increased in the spinal cord after CFA injection. Then, we studied the effect of rapamycin on CFA-induced inflammatory pain in rats, and found that rapamycin restored the autophagy flux and significantly reduced mechanical allodynia and thermal hyperalgesia. In addition, rapamycin significantly decreased the levels of TNF-α, IL-1β, and IL-6 after CFA injection in the spinal cord. CONCLUSION Our results suggested that rapamycin might be a promising candidate for the treatment of inflammatory pain by restoring the autophagy flux in the spinal cord.
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Affiliation(s)
- Jiawei Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China
| | - Shi Chen
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China
| | - Rongyi Zhang
- Department of Pain, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiaoting Zheng
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China
| | - Chang Liu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China
| | - Jiqian Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China
| | - Lei Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China
| | - Zhilai Yang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China
| | - Likui Wang
- Department of Pain, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Hubal A, Vendhoti A, Shaffer CN, Vos S, Corcino YL, Subauste CS. Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt. PLoS Pathog 2025; 21:e1012907. [PMID: 39869638 PMCID: PMC11801697 DOI: 10.1371/journal.ppat.1012907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 02/06/2025] [Accepted: 01/14/2025] [Indexed: 01/29/2025] Open
Abstract
The intracellular protozoan Toxoplasma gondii manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis. This raises the possibility that T. gondii activates a signaling mechanism independently of EGFR to avoid autophagic targeting. We report T. gondii activates Src to promote parasite survival even in cells that lack EGFR. Blockade of Src triggered LC3 and LAMP-1 recruitment around the parasitophorous vacuole (PV) and parasite killing dependent on the autophagy protein, ULK1, and lysosomal enzymes. Src promoted PI3K activation and recruitment of activated Akt to the PV membrane. T. gondii promoted Src association with PTEN, and PTEN phosphorylation at Y240, S380, T382, and T383, hallmarks of an inactive PTEN conformation known to maintain Akt activation. Blockade of parasite killing was dependent of activated Akt. Src knockdown or treatment with the Src family kinase inhibitor, Saracatinib, impaired these events, leading to PTEN accumulation around the PV and a reduction in activated Akt recruitment at this site. Saracatinib treatment in mice with pre-established cerebral and ocular toxoplasmosis promoted PTEN recruitment around tachyzoites in neural tissue impairing recruitment of activated Akt, profoundly reducing parasite load and neural histopathology that were dependent of the autophagy protein, Beclin 1. Our studies uncovered an EGFR-independent pathway activated by T. gondii that enables its survival and is central to the development of neural toxoplasmosis.
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Affiliation(s)
- Alyssa Hubal
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Anusha Vendhoti
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Charles N. Shaffer
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Sarah Vos
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Yalitza Lopez Corcino
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Carlos S. Subauste
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
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Xu C, Wen S, Du X, Zou X, Leung ELH, Zhou G, Wu Q, Shen B. Targeting regulated cell death (RCD) with naturally derived sesquiterpene lactones in cancer therapy. Pharmacol Res 2025; 211:107553. [PMID: 39706282 DOI: 10.1016/j.phrs.2024.107553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024]
Abstract
Regulated cell death (RCD) is a type of cell death modulated by specific signal transduction pathways. Currently, known RCD types include apoptosis, autophagy, ferroptosis, necroptosis, cuproptosis, pyroptosis, and NETosis. Mutations in cancer cells may prevent the RCD pathway; therefore, targeting RCD in tumors has become a promising therapeutic approach. Sesquiterpene lactones represent a diverse and extensive class of plant-derived phytochemicals that serve as potential sources for developing various drugs. Recent studies have shown that sesquiterpene lactones have promising potential in cancer treatment. This review systematically summarizes recent progress in the study of sesquiterpene lactones as antitumor agents, highlighting their role in targeting various RCD pathways, including those involved in apoptosis, autophagy, ferroptosis, necroptosis, and cuproptosis. The primary purpose of the present review is to provide a clear picture of the regulation of RCD by sesquiterpene lactones against different targets in various cancers, which will facilitate the development of new strategies for cancer therapy.
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Affiliation(s)
- Cong Xu
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China; State Key Laboratory of Quality Research in Chinese Medicines and Faculty of Chinese Medicine, Macau University of Science and Technology, 999078, Macao
| | - Shaodi Wen
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China
| | - Xiaoyue Du
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China
| | - Xinhua Zou
- Department of Vascular and Tumor Interventional Medicine, Affiliated Hospital of Jining Medical University, Jining 272000, China
| | | | - Guoren Zhou
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines and Faculty of Chinese Medicine, Macau University of Science and Technology, 999078, Macao.
| | - Bo Shen
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China; DongTai People's Hospital, Dongtai, Jiangsu, China.
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Zhong Y, Shuai Y, Yang J, Zhang M, He T, Zheng L, Yang S, Peng S. LOC730101 improves ovarian cancer drug sensitivity by inhibiting autophagy-mediated DNA damage repair via BECN1. Cell Death Dis 2024; 15:893. [PMID: 39695078 DOI: 10.1038/s41419-024-07278-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024]
Abstract
Drug resistance and recurrence are still the bottlenecks in the clinical treatment of ovarian cancer (OC), seriously affecting patients' prognosis. Therefore, it is an urgent challenge for OC to be overcome towards precision therapy by studying the mechanism of OC drug resistance, finding new drug resistance targets and developing new effective treatment strategies. In this study, we found that lncRNA LOC730101 played an essential role in attenuating drug resistance in OC. LOC730101 was significantly down-regulated in platinum-resistant ovarian cancer tissues, and ectopic overexpression of LOC730101 substantially increased chemotherapy-induced apoptosis. Mechanistically, LOC730101 specifically binds to BECN1 and inhibits the formation of autophagosome BECN1/VPS34 by reducing phosphorylation of BECN1, thereby inhibiting autophagy and promoting drug sensitivity in ovarian cancer cells following treatment with cisplatin and PARP inhibitors. Moreover, LOC730101 inhibits the expression and activity of RNF168 via p62, which in turn affects H2A ubiquitination-mediated DNA damage repair and promotes drug sensitivity in ovarian cancer cells. Our findings demonstrated that LOC730101 played an important role in regulating the formation of the autophagic complex and that inhibition of autophagy significantly enhances the drug sensitivity of OC. And LOC730101 may be used as a prognostic marker to predict the sensitivity of OC to platinum and PARP inhibitors.
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Affiliation(s)
- Yancheng Zhong
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Hunan Key laboratory of Vascular Biology and Translational Medicine, Medical School, Hunan University of Chinese Medicine, Changsha, China
- Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yang Shuai
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Yang
- Department of Gynecologic Oncology Ward 5, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Mojian Zhang
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Tiantian He
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Leliang Zheng
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Sheng Yang
- The Reproductive Medicine Center, The Third Affiliated Hospital of ShenZhen University, Shenzhen Luohu Hospital Group, Shenzhen, China.
| | - Shuping Peng
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan, China.
- Cancer Research Institute, Central South University, Changsha, Hunan, China.
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8
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Rajendran D, Oon CE. Navigating therapeutic prospects by modulating autophagy in colorectal cancer. Life Sci 2024; 358:123121. [PMID: 39389340 DOI: 10.1016/j.lfs.2024.123121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/25/2024] [Accepted: 10/05/2024] [Indexed: 10/12/2024]
Abstract
Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.
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Affiliation(s)
- Deepa Rajendran
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
| | - Chern Ein Oon
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
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9
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Niharika, Garg M. Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance. Expert Rev Mol Med 2024; 26:e23. [PMID: 39375840 PMCID: PMC11488345 DOI: 10.1017/erm.2024.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/25/2023] [Accepted: 06/25/2024] [Indexed: 10/09/2024]
Abstract
Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.
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Affiliation(s)
- Niharika
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
| | - Minal Garg
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
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10
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Wisner SR, Chlebowski M, Mandal A, Mai D, Stein C, Petralia RS, Wang YX, Drerup CM. An initial HOPS-mediated fusion event is critical for autophagosome transport initiation from the axon terminal. Autophagy 2024; 20:2275-2296. [PMID: 38899385 PMCID: PMC11423661 DOI: 10.1080/15548627.2024.2366122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 05/22/2024] [Accepted: 06/05/2024] [Indexed: 06/21/2024] Open
Abstract
In neurons, macroautophagy/autophagy is a frequent and critical process. In the axon, autophagy begins in the axon terminal, where most nascent autophagosomes form. After formation, autophagosomes must initiate transport to exit the axon terminal and move toward the cell body via retrograde transport. During retrograde transport these autophagosomes mature through repetitive fusion events. Complete lysosomal cargo degradation occurs largely in the cell body. The precipitating events to stimulate retrograde autophagosome transport have been debated but their importance is clear: disrupting neuronal autophagy or autophagosome transport is detrimental to neuronal health and function. We have identified the HOPS complex as essential for early autophagosome maturation and consequent initiation of retrograde transport from the axon terminal. In yeast and mammalian cells, HOPS controls fusion between autophagosomes and late endosomes with lysosomes. Using zebrafish strains with loss-of-function mutations in vps18 and vps41, core components of the HOPS complex, we found that disruption of HOPS eliminates autophagosome maturation and disrupts retrograde autophagosome transport initiation from the axon terminal. We confirmed this phenotype was due to loss of HOPS complex formation using an endogenous deletion of the HOPS binding domain in Vps18. Finally, using pharmacological inhibition of lysosomal proteases, we show that initiation of autophagosome retrograde transport requires autophagosome maturation. Together, our data demonstrate that HOPS-mediated fusion events are critical for retrograde autophagosome transport initiation through promoting autophagosome maturation. This reveals critical roles for the HOPS complex in neuronal autophagy which deepens our understanding of the cellular pathology of HOPS-complex linked neurodegenerative diseases.Abbreviations: CORVET: Class C core vacuole/endosome tethering; gRNA: guide RNA; HOPS: homotypic fusion and protein sorting; pLL: posterior lateral line; Vps18: VPS18 core subunit of CORVET and HOPS complexes; Vps41: VPS41 subunit of HOPS complex.
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Affiliation(s)
- Serena R. Wisner
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, USA
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Madison Chlebowski
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, USA
| | - Amrita Mandal
- National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
| | - Don Mai
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, USA
| | - Chris Stein
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, USA
| | - Ronald S. Petralia
- Advanced Imaging Core, National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA
| | - Ya-Xian Wang
- Advanced Imaging Core, National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA
| | - Catherine M. Drerup
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, USA
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA
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11
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Saqirile, Deng Y, Li K, Yan W, Li K, Wang C. Gene Expression Regulation and the Signal Transduction of Programmed Cell Death. Curr Issues Mol Biol 2024; 46:10264-10298. [PMID: 39329964 DOI: 10.3390/cimb46090612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/13/2024] [Accepted: 09/14/2024] [Indexed: 09/28/2024] Open
Abstract
Cell death is of great significance in maintaining tissue homeostasis and bodily functions. With considerable research coming to the fore, it has been found that programmed cell death presents in multiple modalities in the body, which is not only limited to apoptosis, but also can be divided into autophagy, pyroptosis, ferroptosis, mitotic catastrophe, entosis, netosis, and other ways. Different forms of programmed cell death have disparate or analogous characteristics with each other, and their occurrence is accompanied by multiple signal transduction and the role of a myriad of regulatory factors. In recent years, scholars across the world have carried out considerable in-depth research on programmed cell death, and new forms of cell death are being discovered continually. Concomitantly, the mechanisms of intricate signaling pathways and regulators have been discovered. More critically, cancer cells tend to choose distinct ways to evade cell death, and different tumors adapt to different manners of death. Therefore, targeting the cell death network has been regarded as an effective tumor treatment strategy for a long time. The objective of our paper is to review the signaling pathways and gene regulation in several typical types of programmed cell death and their correlation with cancer.
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Affiliation(s)
- Saqirile
- Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science, Inner Mongolia University, 49 Xilingol South Road, Yu Quan District, Hohhot 010020, China
| | - Yuxin Deng
- Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science, Inner Mongolia University, 49 Xilingol South Road, Yu Quan District, Hohhot 010020, China
| | - Kexin Li
- Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science, Inner Mongolia University, 49 Xilingol South Road, Yu Quan District, Hohhot 010020, China
| | - Wenxin Yan
- Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science, Inner Mongolia University, 49 Xilingol South Road, Yu Quan District, Hohhot 010020, China
| | - Ke Li
- Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science, Inner Mongolia University, 49 Xilingol South Road, Yu Quan District, Hohhot 010020, China
| | - Changshan Wang
- Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science, Inner Mongolia University, 49 Xilingol South Road, Yu Quan District, Hohhot 010020, China
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12
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Auddy S, Gupta S, Mandi S, Sharma H, Sinha S, Goswami RK. Total Synthesis of Lipopeptide Bacilotetrin C: Discovery of Potent Anticancer Congeners Promoting Autophagy. ACS Med Chem Lett 2024; 15:1340-1350. [PMID: 39140062 PMCID: PMC11318098 DOI: 10.1021/acsmedchemlett.4c00237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/22/2024] [Accepted: 07/22/2024] [Indexed: 08/15/2024] Open
Abstract
A convergent strategy for the first total synthesis of the lipopeptide bacilotetrin C has been developed. The key features of this synthesis include Crimmins acetate aldol, Steglich esterification, and macrolactamization. Twenty-nine variants of the natural product were prepared following a systematic structure-activity relationship study, where some of the designed analogues showed promising cytotoxic effects against multiple human carcinoma cell lines. The most potent analogue exhibited a ∼37-fold enhancement in cytotoxicity compared to bacilotetrin C in a triple-negative breast cancer (MDA-MB-231) cell line at submicromolar doses. The study further revealed that some of the analogues induced autophagy in cancer cells to the point of their demise at doses much lower than those of known autophagy-inducing peptides. The results demonstrated that the chemical synthesis of bacilotetrin C with suitable improvisation plays an important role in the development of novel anticancer chemotherapeutics, which would allow future rational design of novel autophagy inducers on this template.
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Affiliation(s)
- Sourya
Shankar Auddy
- School
of Chemical Sciences and School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
| | - Shalini Gupta
- School
of Chemical Sciences and School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
| | - Subrata Mandi
- School
of Chemical Sciences and School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
| | - Himangshu Sharma
- School
of Chemical Sciences and School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
| | - Surajit Sinha
- School
of Chemical Sciences and School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
| | - Rajib Kumar Goswami
- School
of Chemical Sciences and School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
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13
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Hassan AMIA, Zhao Y, Chen X, He C. Blockage of Autophagy for Cancer Therapy: A Comprehensive Review. Int J Mol Sci 2024; 25:7459. [PMID: 39000565 PMCID: PMC11242824 DOI: 10.3390/ijms25137459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/25/2024] [Accepted: 07/03/2024] [Indexed: 07/16/2024] Open
Abstract
The incidence and mortality of cancer are increasing, making it a leading cause of death worldwide. Conventional treatments such as surgery, radiotherapy, and chemotherapy face significant limitations due to therapeutic resistance. Autophagy, a cellular self-degradation mechanism, plays a crucial role in cancer development, drug resistance, and treatment. This review investigates the potential of autophagy inhibition as a therapeutic strategy for cancer. A systematic search was conducted on Embase, PubMed, and Google Scholar databases from 1967 to 2024 to identify studies on autophagy inhibitors and their mechanisms in cancer therapy. The review includes original articles utilizing in vitro and in vivo experimental methods, literature reviews, and clinical trials. Key terms used were "Autophagy", "Inhibitors", "Molecular mechanism", "Cancer therapy", and "Clinical trials". Autophagy inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) have shown promise in preclinical studies by inhibiting lysosomal acidification and preventing autophagosome degradation. Other inhibitors like wortmannin and SAR405 target specific components of the autophagy pathway. Combining these inhibitors with chemotherapy has demonstrated enhanced efficacy, making cancer cells more susceptible to cytotoxic agents. Clinical trials involving CQ and HCQ have shown encouraging results, although further investigation is needed to optimize their use in cancer therapy. Autophagy exhibits a dual role in cancer, functioning as both a survival mechanism and a cell death pathway. Targeting autophagy presents a viable strategy for cancer therapy, particularly when integrated with existing treatments. However, the complexity of autophagy regulation and the potential side effects necessitate further research to develop precise and context-specific therapeutic approaches.
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Affiliation(s)
| | - Yuxin Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China (X.C.)
| | - Xiuping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China (X.C.)
- Department of Pharmaceutical Science, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR 999078, China
| | - Chengwei He
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China (X.C.)
- Department of Pharmaceutical Science, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR 999078, China
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14
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McKaige EA, Lee C, Calcinotto V, Giri S, Crawford S, McGrath MJ, Ramm G, Bryson-Richardson RJ. Mitochondrial abnormalities contribute to muscle weakness in a Dnajb6 deficient zebrafish model. Hum Mol Genet 2024; 33:1195-1206. [PMID: 38621658 PMCID: PMC11227618 DOI: 10.1093/hmg/ddae061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/28/2024] [Accepted: 03/28/2024] [Indexed: 04/17/2024] Open
Abstract
Mutations in DNAJB6 are a well-established cause of limb girdle muscular dystrophy type D1 (LGMD D1). Patients with LGMD D1 develop progressive muscle weakness with histology showing fibre damage, autophagic vacuoles, and aggregates. Whilst there are many reports of LGMD D1 patients, the role of DNAJB6 in the muscle is still unclear. In this study, we developed a loss of function zebrafish model in order to investigate the role of Dnajb6. Using a double dnajb6a and dnajb6b mutant model, we show that loss of Dnajb6 leads to a late onset muscle weakness. Interestingly, we find that adult fish lacking Dnajb6 do not have autophagy or myofibril defects, however, they do show mitochondrial changes and damage. This study demonstrates that loss of Dnajb6 causes mitochondrial defects and suggests that this contributes to muscle weakness in LGMD D1. These findings expand our knowledge of the role of Dnajb6 in the muscle and provides a model to screen novel therapies for LGMD D1.
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Affiliation(s)
- Emily A McKaige
- School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia
| | - Clara Lee
- School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia
| | - Vanessa Calcinotto
- School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia
| | - Saveen Giri
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
| | - Simon Crawford
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, 15 Innovation Walk, Clayton, VIC 3800, Australia
| | - Meagan J McGrath
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
| | - Georg Ramm
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, 15 Innovation Walk, Clayton, VIC 3800, Australia
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15
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Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
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Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
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16
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Soto-Avellaneda A, Oxford AE, Halla F, Vasquez P, Oe E, Pugel AD, Schoenfeld AM, Tillman MC, Cuevas A, Ortlund EA, Morrison BE. FABP5-binding lipids regulate autophagy in differentiated SH-SY5Y cells. PLoS One 2024; 19:e0300168. [PMID: 38900831 PMCID: PMC11189175 DOI: 10.1371/journal.pone.0300168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 02/22/2024] [Indexed: 06/22/2024] Open
Abstract
The motor features of Parkinson's disease result from loss of dopaminergic neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. While a large body of work focusing on protein effectors of autophagy has been reported, regulation of autophagy by lipids has garnered far less attention. Therefore, we sought to identify endogenous lipid molecules that act as signaling mediators of autophagy in differentiated SH-SY5Y cells, a commonly used dopaminergic neuron-like cell model. In order to accomplish this goal, we assessed the role of a fatty acid-binding protein (FABP) family member on autophagy due to its function as an intracellular lipid chaperone. We focused specifically upon FABP5 due to its heightened expression in dopaminergic neurons within the substantia nigra and SH-SY5Y cells. Here, we report that knockdown of FABP5 resulted in suppression of autophagy in differentiated SH-SY5Y cells suggesting the possibility of an autophagic role for an interacting lipid. A lipidomic screen of FABP5-interacting lipids uncovered hits that include 5-oxo-eicosatetraenoic acid (5OE) and its precursor metabolite, arachidonic acid (AA). Additionally, other long-chain fatty acids were found to bind FABP5, such as stearic acid (SA), hydroxystearic acid (HSA), and palmitic acid (PA). The addition of 5OE, SA, and HSA but not AA or PA, led to potent inhibition of autophagy in SH-SY5Y cells. To identify potential molecular mechanisms for autophagy inhibition by these lipids, RNA-Seq was performed which revealed both shared and divergent signaling pathways between the lipid-treated groups. These findings suggest a role for these lipids in modulating autophagy through diverse signaling pathways and could represent novel therapeutic targets for Parkinson's disease.
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Affiliation(s)
| | - Alexandra E. Oxford
- Department of Biological Sciences, Boise State University, Boise, ID, United States of America
| | - Fabio Halla
- Department of Biological Sciences, Boise State University, Boise, ID, United States of America
| | - Peyton Vasquez
- Department of Biological Sciences, Boise State University, Boise, ID, United States of America
| | - Emily Oe
- Department of Biological Sciences, Boise State University, Boise, ID, United States of America
| | - Anton D. Pugel
- Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID, United States of America
| | - Alyssa M. Schoenfeld
- Department of Biological Sciences, Boise State University, Boise, ID, United States of America
| | - Matthew C. Tillman
- Department of Biochemistry, Emory University, Atlanta, GA, United States of America
| | - André Cuevas
- Department of Biochemistry, Emory University, Atlanta, GA, United States of America
| | - Eric A. Ortlund
- Department of Biochemistry, Emory University, Atlanta, GA, United States of America
| | - Brad E. Morrison
- Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID, United States of America
- Department of Biological Sciences, Boise State University, Boise, ID, United States of America
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17
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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18
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Dowaidar M. Guidelines for the role of autophagy in drug delivery vectors uptake pathways. Heliyon 2024; 10:e30238. [PMID: 38707383 PMCID: PMC11066435 DOI: 10.1016/j.heliyon.2024.e30238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/22/2024] [Accepted: 04/22/2024] [Indexed: 05/07/2024] Open
Abstract
The process of autophagy refers to the intracellular absorption of cytoplasm (such as proteins, nucleic acids, tiny molecules, complete organelles, and so on) into the lysosome, followed by the breakdown of that cytoplasm. The majority of cellular proteins are degraded by a process called autophagy, which is both a naturally occurring activity and one that may be induced by cellular stress. Autophagy is a system that can save cells' integrity in stressful situations by restoring metabolic basics and getting rid of subcellular junk. This happens as a component of an endurance response. This mechanism may have an effect on disease, in addition to its contribution to the homeostasis of individual cells and tissues as well as the control of development in higher species. The main aim of this study is to discuss the guidelines for the role of autophagy in drug delivery vector uptake pathways. In this paper, we discuss the meaning and concept of autophagy, the mechanism of autophagy, the role of autophagy in drug delivery vectors, autophagy-modulating drugs, nanostructures for delivery systems of autophagy modulators, etc. Later in this paper, we talk about how to deliver chemotherapeutics, siRNA, and autophagy inducers and inhibitors. We also talk about how hard it is to make a drug delivery system that takes nanocarriers' roles as autophagy modulators into account.
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Affiliation(s)
- Moataz Dowaidar
- Bioengineering Department, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran, 31261, Saudi Arabia
- Interdisciplinary Research Center for Hydrogen Technologies and Carbon Management, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran, 31261, Saudi Arabia
- Biosystems and Machines Research Center, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran, 31261, Saudi Arabia
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19
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Wang G, Jiang X, Torabian P, Yang Z. Investigating autophagy and intricate cellular mechanisms in hepatocellular carcinoma: Emphasis on cell death mechanism crosstalk. Cancer Lett 2024; 588:216744. [PMID: 38431037 DOI: 10.1016/j.canlet.2024.216744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/05/2024] [Accepted: 02/18/2024] [Indexed: 03/05/2024]
Abstract
Hepatocellular carcinoma (HCC) stands as a formidable global health challenge due to its prevalence, marked by high mortality and morbidity rates. This cancer type exhibits a multifaceted etiology, prominently linked to viral infections, non-alcoholic fatty liver disease, and genomic mutations. The inherent heterogeneity of HCC, coupled with its proclivity for developing drug resistance, presents formidable obstacles to effective therapeutic interventions. Autophagy, a fundamental catabolic process, plays a pivotal role in maintaining cellular homeostasis, responding to stressors such as nutrient deprivation. In the context of HCC, tumor cells exploit autophagy, either augmenting or impeding its activity, thereby influencing tumorigenesis. This comprehensive review underscores the dualistic role of autophagy in HCC, acting as both a pro-survival and pro-death mechanism, impacting the trajectory of tumorigenesis. The anti-carcinogenic potential of autophagy is evident in its ability to enhance apoptosis and ferroptosis in HCC cells. Pertinently, dysregulated autophagy fosters drug resistance in the carcinogenic context. Both genomic and epigenetic factors can regulate autophagy in HCC progression. Recognizing the paramount importance of autophagy in HCC progression, this review introduces pharmacological compounds capable of modulating autophagy-either inducing or inhibiting it, as promising avenues in HCC therapy.
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Affiliation(s)
- Gang Wang
- Department of Interventional, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Xiaodi Jiang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, 110020, PR China
| | - Pedram Torabian
- Arnie Charbonneau Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada; Department of Medical Sciences, University of Calgary, Calgary, AB, T2N 4Z6, Canada.
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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20
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Ortega MA, Fraile-Martinez O, de Leon-Oliva D, Boaru DL, Lopez-Gonzalez L, García-Montero C, Alvarez-Mon MA, Guijarro LG, Torres-Carranza D, Saez MA, Diaz-Pedrero R, Albillos A, Alvarez-Mon M. Autophagy in Its (Proper) Context: Molecular Basis, Biological Relevance, Pharmacological Modulation, and Lifestyle Medicine. Int J Biol Sci 2024; 20:2532-2554. [PMID: 38725847 PMCID: PMC11077378 DOI: 10.7150/ijbs.95122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/04/2024] [Indexed: 05/12/2024] Open
Abstract
Autophagy plays a critical role in maintaining cellular homeostasis and responding to various stress conditions by the degradation of intracellular components. In this narrative review, we provide a comprehensive overview of autophagy's cellular and molecular basis, biological significance, pharmacological modulation, and its relevance in lifestyle medicine. We delve into the intricate molecular mechanisms that govern autophagy, including macroautophagy, microautophagy and chaperone-mediated autophagy. Moreover, we highlight the biological significance of autophagy in aging, immunity, metabolism, apoptosis, tissue differentiation and systemic diseases, such as neurodegenerative or cardiovascular diseases and cancer. We also discuss the latest advancements in pharmacological modulation of autophagy and their potential implications in clinical settings. Finally, we explore the intimate connection between lifestyle factors and autophagy, emphasizing how nutrition, exercise, sleep patterns and environmental factors can significantly impact the autophagic process. The integration of lifestyle medicine into autophagy research opens new avenues for promoting health and longevity through personalized interventions.
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Affiliation(s)
- Miguel A Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Diego de Leon-Oliva
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Laura Lopez-Gonzalez
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Miguel Angel Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Luis G Guijarro
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcalá, 28801 Alcala de Henares, Spain
| | - Diego Torres-Carranza
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Miguel A Saez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, 28801 Alcala de Henares, Spain
| | - Raul Diaz-Pedrero
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Department of General and Digestive Surgery, Príncipe de Asturias Universitary Hospital, 28805 Alcala de Henares, Spain
| | - Agustin Albillos
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine (CIBEREHD), Príncipe de Asturias University Hospital, 28806 Alcala de Henares, Spain
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21
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Zhou XC, Wang DX, Zhang CY, Yang YJ, Zhao RB, Liu SY, Ni GX. Exercise promotes osteogenic differentiation by activating the long non-coding RNA H19/microRNA-149 axis. World J Orthop 2024; 15:363-378. [PMID: 38680671 PMCID: PMC11045468 DOI: 10.5312/wjo.v15.i4.363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/04/2024] [Accepted: 03/19/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Regular physical activity during childhood and adolescence is beneficial to bone development, as evidenced by the ability to increase bone density and peak bone mass by promoting bone formation. AIM To investigate the effects of exercise on bone formation in growing mice and to investigate the underlying mechanisms. METHODS 20 growing mice were randomly divided into two groups: Con group (control group, n = 10) and Ex group (treadmill exercise group, n = 10). Hematoxylin-eosin staining, immunohistochemistry, and micro-CT scanning were used to assess the bone formation-related indexes of the mouse femur. Bioinformatics analysis was used to find potential miRNAs targets of long non-coding RNA H19 (lncRNA H19). RT-qPCR and Western Blot were used to confirm potential miRNA target genes of lncRNA H19 and the role of lncRNA H19 in promoting osteogenic differentiation. RESULTS Compared with the Con group, the expression of bone morphogenetic protein 2 was also significantly increased. The micro-CT results showed that 8 wk moderate-intensity treadmill exercise significantly increased bone mineral density, bone volume fraction, and the number of trabeculae, and decreased trabecular segregation in the femur of mice. Inhibition of lncRNA H19 significantly upregulated the expression of miR-149 and suppressed the expression of markers of osteogenic differentiation. In addition, knockdown of lncRNA H19 significantly downregulated the expression of autophagy markers, which is consistent with the results of autophagy-related protein changes detected in mouse femurs by immunofluorescence. CONCLUSION Appropriate treadmill exercise can effectively stimulate bone formation and promote the increase of bone density and bone volume in growing mice, thus enhancing the peak bone mass of mice. The lncRNA H19/miR-149 axis plays an important regulatory role in osteogenic differentiation.
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Affiliation(s)
- Xu-Chang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Dong-Xue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Chun-Yu Zhang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Ya-Jing Yang
- Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Ruo-Bing Zhao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Sheng-Yao Liu
- Department of Spinal Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Guo-Xin Ni
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
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22
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Florance I, Cordani M, Pashootan P, Moosavi MA, Zarrabi A, Chandrasekaran N. The impact of nanomaterials on autophagy across health and disease conditions. Cell Mol Life Sci 2024; 81:184. [PMID: 38630152 PMCID: PMC11024050 DOI: 10.1007/s00018-024-05199-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 03/01/2024] [Accepted: 03/03/2024] [Indexed: 04/19/2024]
Abstract
Autophagy, a catabolic process integral to cellular homeostasis, is constitutively active under physiological and stress conditions. The role of autophagy as a cellular defense response becomes particularly evident upon exposure to nanomaterials (NMs), especially environmental nanoparticles (NPs) and nanoplastics (nPs). This has positioned autophagy modulation at the forefront of nanotechnology-based therapeutic interventions. While NMs can exploit autophagy to enhance therapeutic outcomes, they can also trigger it as a pro-survival response against NP-induced toxicity. Conversely, a heightened autophagy response may also lead to regulated cell death (RCD), in particular autophagic cell death, upon NP exposure. Thus, the relationship between NMs and autophagy exhibits a dual nature with therapeutic and environmental interventions. Recognizing and decoding these intricate patterns are essential for pioneering next-generation autophagy-regulating NMs. This review delves into the present-day therapeutic potential of autophagy-modulating NMs, shedding light on their status in clinical trials, intervention of autophagy in the therapeutic applications of NMs, discusses the potency of autophagy for application as early indicator of NM toxicity.
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Affiliation(s)
- Ida Florance
- Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Parya Pashootan
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Mohammad Amin Moosavi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, India
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan, Taiwan
| | - Natarajan Chandrasekaran
- Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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23
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Wójciuk KE, Sadło J, Lewandowska H, Brzóska K, Kruszewski M. A Crucial Role of Proteolysis in the Formation of Intracellular Dinitrosyl Iron Complexes. Molecules 2024; 29:1630. [PMID: 38611909 PMCID: PMC11013114 DOI: 10.3390/molecules29071630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Dinitrosyl iron complexes (DNICs) stabilize nitric oxide in cells and tissues and constitute an important form of its storage and transportation. DNICs may comprise low-molecular-weight ligands, e.g., thiols, imidazole groups in chemical compounds with low molecular weight (LMWDNICs), or high-molecular-weight ligands, e.g., peptides or proteins (HMWDNICs). The aim of this study was to investigate the role of low- and high-molecular-weight ligands in DNIC formation. Lysosomal and proteasomal proteolysis was inhibited by specific inhibitors. Experiments were conducted on human erythroid K562 cells and on K562 cells overexpressing a heavy chain of ferritin. Cell cultures were treated with •NO donor. DNIC formation was monitored by electron paramagnetic resonance. Pretreatment of cells with proteolysis inhibitors diminished the intensity and changed the shape of the DNIC-specific EPR signal in a treatment time-dependent manner. The level of DNIC formation was significantly influenced by the presence of protein degradation products. Interestingly, formation of HMWDNICs depended on the availability of LMWDNICs. The extent of glutathione involvement in the in vivo formation of DNICs is minor yet noticeable, aligning with our prior research findings.
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Affiliation(s)
- Karolina E. Wójciuk
- Nuclear Facilities Operations Department, National Centre for Nuclear Research (NCBJ), 05-400 Otwock, Poland
- Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland; (H.L.); (K.B.); (M.K.)
| | - Jarosław Sadło
- Centre for Radiation Chemistry and Technology, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland;
| | - Hanna Lewandowska
- Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland; (H.L.); (K.B.); (M.K.)
- School of Health & Medical Sciences, University of Economics and Human Sciences in Warsaw, 59 Okopowa St., 01-043 Warsaw, Poland
| | - Kamil Brzóska
- Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland; (H.L.); (K.B.); (M.K.)
| | - Marcin Kruszewski
- Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland; (H.L.); (K.B.); (M.K.)
- Department of Molecular Biology and Translational Research, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland
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24
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Sun C, Zhan J, Li Y, Zhou C, Huang S, Zhu X, Huang K. Non-apoptotic regulated cell death mediates reprogramming of the tumour immune microenvironment by macrophages. J Cell Mol Med 2024; 28:e18348. [PMID: 38652105 PMCID: PMC11037416 DOI: 10.1111/jcmm.18348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 02/23/2024] [Accepted: 04/08/2024] [Indexed: 04/25/2024] Open
Abstract
Tumour immune microenvironment (TIME) plays an indispensable role in tumour progression, and tumour-associated macrophages (TAMs) are the most abundant immune cells in TIME. Non-apoptotic regulated cell death (RCD) can avoid the influence of tumour apoptosis resistance on anti-tumour immune response. Specifically, autophagy, ferroptosis, pyroptosis and necroptosis mediate the crosstalk between TAMs and tumour cells in TIME, thus reprogram TIME and affect the progress of tumour. In addition, although some achievements have been made in immune checkpoint inhibitors (ICIs), there is still defect that ICIs are only effective for some people because non-apoptotic RCD can bypass the apoptosis resistance of tumour. As a result, ICIs combined with targeting non-apoptotic RCD may be a promising solution. In this paper, the basic molecular mechanism of non-apoptotic RCD, the way in which non-apoptotic RCD mediates crosstalk between TAMs and tumour cells to reprogram TIME, and the latest research progress in targeting non-apoptotic RCD and ICIs are reviewed.
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Affiliation(s)
- Chengpeng Sun
- Department of NeurosurgeryThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- HuanKui Academy, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Jianhao Zhan
- HuanKui Academy, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Yao Li
- The First Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Chulin Zhou
- The Second Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Shuo Huang
- The Second Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Xingen Zhu
- Department of NeurosurgeryThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular DiseasesNanchangChina
- JXHC Key Laboratory of Neurological MedicineNanchangJiangxiP. R. China
| | - Kai Huang
- Department of NeurosurgeryThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular DiseasesNanchangChina
- JXHC Key Laboratory of Neurological MedicineNanchangJiangxiP. R. China
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25
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McGrath MK, Abolhassani A, Guy L, Elshazly AM, Barrett JT, Mivechi NF, Gewirtz DA, Schoenlein PV. Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer. Front Endocrinol (Lausanne) 2024; 15:1298423. [PMID: 38567308 PMCID: PMC10986181 DOI: 10.3389/fendo.2024.1298423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 02/26/2024] [Indexed: 04/04/2024] Open
Abstract
Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.
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Affiliation(s)
- Michael K. McGrath
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Ali Abolhassani
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Luke Guy
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Ahmed M. Elshazly
- Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - John T. Barrett
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Radiation Oncology, Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Nahid F. Mivechi
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Radiation Oncology, Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - David A. Gewirtz
- Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Patricia V. Schoenlein
- Georgia Cancer Center, Augusta University, Augusta, GA, United States
- Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
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Liu B, Yao X, Shang Y, Dai J. The multiple roles of autophagy in uveal melanoma and the microenvironment. J Cancer Res Clin Oncol 2024; 150:121. [PMID: 38467935 PMCID: PMC10927889 DOI: 10.1007/s00432-023-05576-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 11/09/2023] [Indexed: 03/13/2024]
Abstract
PURPOSE Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults, and effective clinical treatment strategies are still lacking. Autophagy is a lysosome-dependent degradation system that can encapsulate abnormal proteins, damaged organelles. However, dysfunctional autophagy has multiple types and plays a complex role in tumorigenicity depending on many factors, such as tumor stage, microenvironment, signaling pathway activation, and application of autophagic drugs. METHODS A systematic review of the literature was conducted to analyze the role of autophagy in UM, as well as describing the development of autophagic drugs and the link between autophagy and the tumor microenvironment. RESULTS In this review, we summarize current research advances regarding the types of autophagy, the mechanisms of autophagy, the application of autophagy inhibitors or agonists, autophagy and the tumor microenvironment. Finally, we also discuss the relationship between autophagy and UM. CONCLUSION Understanding the molecular mechanisms of how autophagy differentially affects tumor progression may help to design better therapeutic regimens to prevent and treat UM.
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Affiliation(s)
- Bo Liu
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Xueting Yao
- Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Shang
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Jinhui Dai
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.
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27
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Jiang M, Wu W, Xiong Z, Yu X, Ye Z, Wu Z. Targeting autophagy drug discovery: Targets, indications and development trends. Eur J Med Chem 2024; 267:116117. [PMID: 38295689 DOI: 10.1016/j.ejmech.2023.116117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/30/2023] [Accepted: 12/31/2023] [Indexed: 02/25/2024]
Abstract
Autophagy plays a vital role in sustaining cellular homeostasis and its alterations have been implicated in the etiology of many diseases. Drugs development targeting autophagy began decades ago and hundreds of agents were developed, some of which are licensed for the clinical usage. However, no existing intervention specifically aimed at modulating autophagy is available. The obstacles that prevent drug developments come from the complexity of the actual impact of autophagy regulators in disease scenarios. With the development and application of new technologies, several promising categories of compounds for autophagy-based therapy have emerged in recent years. In this paper, the autophagy-targeted drugs based on their targets at various hierarchical sites of the autophagic signaling network, e.g., the upstream and downstream of the autophagosome and the autophagic components with enzyme activities are reviewed and analyzed respectively, with special attention paid to those at preclinical or clinical trials. The drugs tailored to specific autophagy alone and combination with drugs/adjuvant therapies widely used in clinical for various diseases treatments are also emphasized. The emerging drug design and development targeting selective autophagy receptors (SARs) and their related proteins, which would be expected to arrest or reverse the progression of disease in various cancers, inflammation, neurodegeneration, and metabolic disorders, are critically reviewed. And the challenges and perspective in clinically developing autophagy-targeted drugs and possible combinations with other medicine are considered in the review.
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Affiliation(s)
- Mengjia Jiang
- Department of Pharmacology and Pharmacy, China Jiliang University, China
| | - Wayne Wu
- College of Osteopathic Medicine, New York Institute of Technology, USA
| | - Zijie Xiong
- Department of Pharmacology and Pharmacy, China Jiliang University, China
| | - Xiaoping Yu
- Department of Biology, China Jiliang University, China
| | - Zihong Ye
- Department of Biology, China Jiliang University, China
| | - Zhiping Wu
- Department of Pharmacology and Pharmacy, China Jiliang University, China.
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28
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Tiwari M, Srivastava P, Abbas S, Jegatheesan J, Ranjan A, Sharma S, Maurya VP, Saxena AK, Sharma LK. Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells. Cells 2024; 13:447. [PMID: 38474411 PMCID: PMC10930960 DOI: 10.3390/cells13050447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Tumors are composed of heterogeneous populations of dysregulated cells that grow in specialized niches that support their growth and maintain their properties. Tumor heterogeneity and metastasis are among the major hindrances that exist while treating cancer patients, leading to poor clinical outcomes. Although the factors that determine tumor complexity remain largely unknown, several genotypic and phenotypic changes, including DNA mutations and metabolic reprograming provide cancer cells with a survival advantage over host cells and resistance to therapeutics. Furthermore, the presence of a specific population of cells within the tumor mass, commonly known as cancer stem cells (CSCs), is thought to initiate tumor formation, maintenance, resistance, and recurrence. Therefore, these CSCs have been investigated in detail recently as potential targets to treat cancer and prevent recurrence. Understanding the molecular mechanisms involved in CSC proliferation, self-renewal, and dormancy may provide important clues for developing effective therapeutic strategies. Autophagy, a catabolic process, has long been recognized to regulate various physiological and pathological processes. In addition to regulating cancer cells, recent studies have identified a critical role for autophagy in regulating CSC functions. Autophagy is activated under various adverse conditions and promotes cellular maintenance, survival, and even cell death. Thus, it is intriguing to address whether autophagy promotes or inhibits CSC functions and whether autophagy modulation can be used to regulate CSC functions, either alone or in combination. This review describes the roles of autophagy in the regulation of metabolic functions, proliferation and quiescence of CSCs, and its role during therapeutic stress. The review further highlights the autophagy-associated pathways that could be used to regulate CSCs. Overall, the present review will help to rationalize various translational approaches that involve autophagy-mediated modulation of CSCs in controlling cancer progression, metastasis, and recurrence.
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Affiliation(s)
- Meenakshi Tiwari
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Pransu Srivastava
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow 226014, India
| | - Sabiya Abbas
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow 226014, India
| | - Janani Jegatheesan
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Ashish Ranjan
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Sadhana Sharma
- Department of Biochemistry, All India Institute of Medical Science, Patna 801507, India
| | - Ved Prakash Maurya
- Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Ajit Kumar Saxena
- Department of Pathology/Lab Medicine, All India Institute of Medical Science, Patna 801507, India
| | - Lokendra Kumar Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow 226014, India
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Zhang Y, Yang J, Ouyang C, Meng N. The association between ferroptosis and autophagy in cardiovascular diseases. Cell Biochem Funct 2024; 42:e3985. [PMID: 38509716 DOI: 10.1002/cbf.3985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/22/2024]
Abstract
Autophagy is a process in which cells degrade intracellular substances and play a variety of roles in cells, such as maintaining intracellular homeostasis, preventing cell overgrowth, and removing pathogens. It is highly conserved during the evolution of eukaryotic cells. So far, the study of autophagy is still a hot topic in the field of cytology. Ferroptosis is an iron-dependent form of cell death, accompanied by the accumulation of reactive oxygen species and lipid peroxides. With the deepening of research, it has been found that ferroptosis, like autophagy, is involved in the occurrence and development of cardiovascular diseases. The relationship between autophagy and ferroptosis is complex, and the association between the two in cardiovascular disease remains to be clarified. This article reviews the mechanism of autophagy and ferroptosis and their correlation, and discusses the relationship between them in cardiovascular diseases, which is expected to provide new and important treatment strategies for cardiovascular diseases.
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Affiliation(s)
- Yifan Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, China
| | - Junjun Yang
- School of Biological Science and Technology, University of Jinan, Jinan, China
| | - Chenxi Ouyang
- Department of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Meng
- School of Biological Science and Technology, University of Jinan, Jinan, China
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30
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Grifagni D, Silva JM, Querci L, Lepoivre M, Vallières C, Louro RO, Banci L, Piccioli M, Golinelli-Cohen MP, Cantini F. Biochemical and cellular characterization of the CISD3 protein: Molecular bases of cluster release and destabilizing effects of nitric oxide. J Biol Chem 2024; 300:105745. [PMID: 38354784 PMCID: PMC10937110 DOI: 10.1016/j.jbc.2024.105745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 02/02/2024] [Accepted: 02/05/2024] [Indexed: 02/16/2024] Open
Abstract
The NEET proteins, an important family of iron-sulfur (Fe-S) proteins, have generated a strong interest due to their involvement in diverse diseases such as cancer, diabetes, and neurodegenerative disorders. Among the human NEET proteins, CISD3 has been the least studied, and its functional role is still largely unknown. We have investigated the biochemical features of CISD3 at the atomic and in cellulo levels upon challenge with different stress conditions i.e., iron deficiency, exposure to hydrogen peroxide, and nitric oxide. The redox and cellular stability properties of the protein agree on a predominance of reduced form of CISD3 in the cells. Upon the addition of iron chelators, CISD3 loses its Fe-S clusters and becomes unstructured, and its cellular level drastically decreases. Chemical shift perturbation measurements suggest that, upon cluster oxidation, the protein undergoes a conformational change at the C-terminal CDGSH domain, which determines the instability of the oxidized state. This redox-associated conformational change may be the source of cooperative electron transfer via the two [Fe2S2] clusters in CISD3, which displays a single sharp voltammetric signal at -31 mV versus SHE. Oxidized CISD3 is particularly sensitive to the presence of hydrogen peroxide in vitro, whereas only the reduced form is able to bind nitric oxide. Paramagnetic NMR provides clear evidence that, upon NO binding, the cluster is disassembled but iron ions are still bound to the protein. Accordingly, in cellulo CISD3 is unaffected by oxidative stress induced by hydrogen peroxide but it becomes highly unstable in response to nitric oxide treatment.
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Affiliation(s)
- Deborah Grifagni
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy
| | - José Malanho Silva
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy
| | - Leonardo Querci
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy
| | - Michel Lepoivre
- CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Université Paris-Saclay, Gif-sur-Yvette, France
| | - Cindy Vallières
- CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Université Paris-Saclay, Gif-sur-Yvette, France
| | - Ricardo O Louro
- Instituto de Tecnologia Química e Biológica António Xavier (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Lucia Banci
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy
| | - Mario Piccioli
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy.
| | | | - Francesca Cantini
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Sesto Fiorentino, Italy.
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31
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Huang YK, Cheng WC, Kuo TT, Yang JC, Wu YC, Wu HH, Lo CC, Hsieh CY, Wong SC, Lu CH, Wu WL, Liu SJ, Li YC, Lin CC, Shen CN, Hung MC, Lin JT, Yeh CC, Sher YP. Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy. NATURE CANCER 2024; 5:400-419. [PMID: 38267627 DOI: 10.1038/s43018-023-00720-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 12/19/2023] [Indexed: 01/26/2024]
Abstract
Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.
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Affiliation(s)
- Yu-Kai Huang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Wei-Chung Cheng
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan
- Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan
| | - Ting-Ting Kuo
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Juan-Cheng Yang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Yang-Chang Wu
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | - Heng-Hsiung Wu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Chia-Chien Lo
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Ying Hsieh
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Sze-Ching Wong
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Chih-Hao Lu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wan-Ling Wu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
| | - Shih-Jen Liu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Chuan Li
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Ching-Chan Lin
- Division of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Ning Shen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mien-Chie Hung
- Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jaw-Town Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Chun-Chieh Yeh
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan.
- Department of Surgery, Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan.
| | - Yuh-Pyng Sher
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
- Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan.
- Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
- Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, Taiwan.
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32
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Kang H, Kang T, Jackson L, Murphy A, Nitta T. Evidence for Involvement of ADP-Ribosylation Factor 6 in Intracellular Trafficking and Release of Murine Leukemia Virus Gag. Cells 2024; 13:270. [PMID: 38334661 PMCID: PMC10854678 DOI: 10.3390/cells13030270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024] Open
Abstract
Murine leukemia viruses (MuLVs) are simple retroviruses that cause several diseases in mice. Retroviruses encode three basic genes: gag, pol, and env. Gag is translated as a polyprotein and moves to assembly sites where viral particles are shaped by cleavage of poly-Gag. Viral release depends on the intracellular trafficking of viral proteins, which is determined by both viral and cellular factors. ADP-ribosylation factor 6 (Arf6) is a small GTPase that regulates vesicular trafficking and recycling of different types of cargo in cells. Arf6 also activates phospholipase D (PLD) and phosphatidylinositol-4-phosphate 5-kinase (PIP5K) and produces phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). We investigated how Arf6 affected MuLV release with a constitutively active form of Arf6, Arf6Q67L. Expression of Arf6Q67L impaired Gag release by accumulating Gag at PI(4,5)P2-enriched compartments in the cytoplasm. Treatment of the inhibitors for PLD and PIP5K impaired or recovered MuLV Gag release in the cells expressing GFP (control) and Arf6Q67L, implying that regulation of PI(4,5)P2 through PLD and PIP5K affected MuLV release. Interference with the phosphoinositide 3-kinases, mammalian target of rapamycin (mTOR) pathway, and vacuolar-type ATPase activities showed further impairment of Gag release from the cells expressing Arf6Q67L. In contrast, mTOR inhibition increased Gag release in the control cells. The proteasome inhibitors reduced viral release in the cells regardless of Arf6Q67L expression. These data outline the differences in MuLV release under the controlled and overactivated Arf6 conditions and provide new insight into pathways for MuLV release.
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Affiliation(s)
- Hyokyun Kang
- Department of Biology, Savannah State University, Savannah, GA 31404, USA; (H.K.); (T.K.); (L.J.); (A.M.)
| | - Taekwon Kang
- Department of Biology, Savannah State University, Savannah, GA 31404, USA; (H.K.); (T.K.); (L.J.); (A.M.)
| | - Lauryn Jackson
- Department of Biology, Savannah State University, Savannah, GA 31404, USA; (H.K.); (T.K.); (L.J.); (A.M.)
| | - Amaiya Murphy
- Department of Biology, Savannah State University, Savannah, GA 31404, USA; (H.K.); (T.K.); (L.J.); (A.M.)
| | - Takayuki Nitta
- Department of Biology, Savannah State University, Savannah, GA 31404, USA; (H.K.); (T.K.); (L.J.); (A.M.)
- Department of Molecular Biology and Biochemistry, Cancer Research Institute, University of California, Irvine, CA 92697, USA
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33
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Beilankouhi EAV, Valilo M, Dastmalchi N, Teimourian S, Safaralizadeh R. The Function of Autophagy in the Initiation, and Development of Breast Cancer. Curr Med Chem 2024; 31:2974-2990. [PMID: 37138421 DOI: 10.2174/0929867330666230503145319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/26/2021] [Accepted: 03/15/2021] [Indexed: 05/05/2023]
Abstract
Autophagy is a significant catabolic procedure that increases in stressful conditions. This mechanism is mostly triggered after damage to the organelles, the presence of unnatural proteins, and nutrient recycling in reaction to these stresses. One of the key points in this article is that cleaning and preserving damaged organelles and accumulated molecules through autophagy in normal cells helps prevent cancer. Since dysfunction of autophagy is associated with various diseases, including cancer, it has a dual function in tumor suppression and expansion. It has newly become clear that the regulation of autophagy can be used for the treatment of breast cancer, which has a promising effect of increasing the efficiency of anticancer treatment in a tissue- and cell-type-specific manner by affecting the fundamental molecular mechanisms. Regulation of autophagy and its function in tumorigenesis is a vital part of modern anticancer techniques. This study discusses the current advances related to the mechanisms that describe essential modulators of autophagy involved in the metastasis of cancers and the development of new breast cancer treatments.
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Affiliation(s)
| | - Mohammad Valilo
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Narges Dastmalchi
- Department of Biology, University College of Nabi Akram, Tabriz, Iran
| | - Shahram Teimourian
- Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
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34
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Fares J, Petrosyan E, Kanojia D, Dmello C, Cordero A, Duffy JT, Yeeravalli R, Sahani MH, Zhang P, Rashidi A, Arrieta VA, Ulasov I, Ahmed AU, Miska J, Balyasnikova IV, James CD, Sonabend AM, Heimberger AB, Lesniak MS. Metixene is an incomplete autophagy inducer in preclinical models of metastatic cancer and brain metastases. J Clin Invest 2023; 133:e161142. [PMID: 37847564 PMCID: PMC10721147 DOI: 10.1172/jci161142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 10/12/2023] [Indexed: 10/18/2023] Open
Abstract
A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation.
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Affiliation(s)
- Jawad Fares
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Edgar Petrosyan
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Deepak Kanojia
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Crismita Dmello
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Alex Cordero
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Joseph T. Duffy
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ragini Yeeravalli
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Mayurbhai H. Sahani
- Dr. Vikram Sarabhai Institute of Cell and Molecular Biology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
| | - Peng Zhang
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Aida Rashidi
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Victor A. Arrieta
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ilya Ulasov
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Atique U. Ahmed
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jason Miska
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Irina V. Balyasnikova
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - C. David James
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Adam M. Sonabend
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Amy B. Heimberger
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Maciej S. Lesniak
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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Julio AR, Shikwana F, Truong C, Burton NR, Dominguez E, Turmon AC, Cao J, Backus K. Pervasive aggregation and depletion of host and viral proteins in response to cysteine-reactive electrophilic compounds. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.30.564067. [PMID: 38014036 PMCID: PMC10680658 DOI: 10.1101/2023.10.30.564067] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Protein homeostasis is tightly regulated, with damaged or misfolded proteins quickly eliminated by the proteasome and autophagosome pathways. By co-opting these processes, targeted protein degradation technologies enable pharmacological manipulation of protein abundance. Recently, cysteine-reactive molecules have been added to the degrader toolbox, which offer the benefit of unlocking the therapeutic potential of 'undruggable' protein targets. The proteome-wide impact of these molecules remains to be fully understood and given the general reactivity of many classes of cysteine-reactive electrophiles, on- and off-target effects are likely. Using chemical proteomics, we identified a cysteine-reactive small molecule degrader of the SARS-CoV-2 nonstructural protein 14 (nsp14), which effects degradation through direct modification of cysteines in both nsp14 and in host chaperones together with activation of global cell stress response pathways. We find that cysteine-reactive electrophiles increase global protein ubiquitylation, trigger proteasome activation, and result in widespread aggregation and depletion of host proteins, including components of the nuclear pore complex. Formation of stress granules was also found to be a remarkably ubiquitous cellular response to nearly all cysteine-reactive compounds and degraders. Collectively, our study sheds light on complexities of covalent target protein degradation and highlights untapped opportunities in manipulating and characterizing proteostasis processes via deciphering the cysteine-centric regulation of stress response pathways.
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Affiliation(s)
- Ashley R Julio
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095 (USA)
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095 (USA)
| | - Flowreen Shikwana
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095 (USA)
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095 (USA)
| | - Cindy Truong
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095 (USA)
| | - Nikolas R Burton
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095 (USA)
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095 (USA)
| | - Emil Dominguez
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095 (USA)
| | - Alexandra C Turmon
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095 (USA)
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095 (USA)
| | - Jian Cao
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095 (USA)
| | - Keriann Backus
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095 (USA)
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095 (USA)
- DOE Institute for Genomics and Proteomics, UCLA, Los Angeles, CA 90095 (USA)
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095 (USA)
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095 (USA)
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36
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Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions. Int J Mol Sci 2023; 24:16255. [PMID: 38003445 PMCID: PMC10671265 DOI: 10.3390/ijms242216255] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
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Affiliation(s)
- Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | | | - Taesik You
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
- Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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Yoon J, Min CW, Kim J, Baek G, Kim D, Jang JW, Gupta R, Kim ST, Cho LH. Quantitative Proteomic Analysis Deciphers the Molecular Mechanism for Endosperm Nuclear Division in Early Rice Seed Development. PLANTS (BASEL, SWITZERLAND) 2023; 12:3715. [PMID: 37960070 PMCID: PMC10650807 DOI: 10.3390/plants12213715] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 10/26/2023] [Accepted: 10/27/2023] [Indexed: 11/15/2023]
Abstract
Understanding the molecular mechanisms underlying early seed development is important in improving the grain yield and quality of crop plants. We performed a comparative label-free quantitative proteomic analysis of developing rice seeds for the WT and osctps1-2 mutant, encoding a cytidine triphosphate synthase previously reported as the endospermless 2 (enl2) mutant in rice, harvested at 0 and 1 d after pollination (DAP) to understand the molecular mechanism of early seed development. In total, 5231 proteins were identified, of which 902 changed in abundance between 0 and 1 DAP seeds. Proteins that preferentially accumulated at 1 DAP were involved in DNA replication and pyrimidine biosynthetic pathways. Notably, an increased abundance of OsCTPS1 was observed at 1 DAP; however, no such changes were observed at the transcriptional level. We further observed that the inhibition of phosphorylation increased the stability of this protein. Furthermore, in osctps1-2, minichromosome maintenance (MCM) proteins were significantly reduced compared with those in the WT at 1 DAP, and mutations in OsMCM5 caused defects in seed development. These results highlight the molecular mechanisms underlying early seed development in rice at the post-transcriptional level.
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Affiliation(s)
- Jinmi Yoon
- Department of Biological Sciences, Inha University, Incheon 22212, Republic of Korea;
- Department of Biological Sciences and Bioengineering, Industry-Academia Interactive R&E Center for Bioprocess Innovation, Inha University, Incheon 22212, Republic of Korea
| | - Cheol Woo Min
- Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Republic of Korea;
| | - Jiyoung Kim
- Department of Plant Bioscience, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (J.K.); (G.B.); (D.K.); (J.W.J.)
| | - Gibeom Baek
- Department of Plant Bioscience, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (J.K.); (G.B.); (D.K.); (J.W.J.)
| | - Dohyeon Kim
- Department of Plant Bioscience, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (J.K.); (G.B.); (D.K.); (J.W.J.)
| | - Jeong Woo Jang
- Department of Plant Bioscience, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (J.K.); (G.B.); (D.K.); (J.W.J.)
| | - Ravi Gupta
- College of General Education, Kookmin University, Seoul 02707, Republic of Korea;
| | - Sun Tae Kim
- Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Republic of Korea;
- Department of Plant Bioscience, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (J.K.); (G.B.); (D.K.); (J.W.J.)
| | - Lae-Hyeon Cho
- Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Republic of Korea;
- Department of Plant Bioscience, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea; (J.K.); (G.B.); (D.K.); (J.W.J.)
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de Jesus VHF, Mathias-Machado MC, de Farias JPF, Aruquipa MPS, Jácome AA, Peixoto RD. Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure. Cancers (Basel) 2023; 15:5015. [PMID: 37894382 PMCID: PMC10605759 DOI: 10.3390/cancers15205015] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/04/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.
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Affiliation(s)
| | | | | | | | - Alexandre A. Jácome
- Department of Gastrointestinal Medical Oncology, Oncoclínicas, Belo Horizonte 30360-680, Brazil
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Chueh KS, Lu JH, Juan TJ, Chuang SM, Juan YS. The Molecular Mechanism and Therapeutic Application of Autophagy for Urological Disease. Int J Mol Sci 2023; 24:14887. [PMID: 37834333 PMCID: PMC10573233 DOI: 10.3390/ijms241914887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/25/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Autophagy is a lysosomal degradation process known as autophagic flux, involving the engulfment of damaged proteins and organelles by double-membrane autophagosomes. It comprises microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy. Macroautophagy consists of three stages: induction, autophagosome formation, and autolysosome formation. Atg8-family proteins are valuable for tracking autophagic structures and have been widely utilized for monitoring autophagy. The conversion of LC3 to its lipidated form, LC3-II, served as an indicator of autophagy. Autophagy is implicated in human pathophysiology, such as neurodegeneration, cancer, and immune disorders. Moreover, autophagy impacts urological diseases, such as interstitial cystitis /bladder pain syndrome (IC/BPS), ketamine-induced ulcerative cystitis (KIC), chemotherapy-induced cystitis (CIC), radiation cystitis (RC), erectile dysfunction (ED), bladder outlet obstruction (BOO), prostate cancer, bladder cancer, renal cancer, testicular cancer, and penile cancer. Autophagy plays a dual role in the management of urologic diseases, and the identification of potential biomarkers associated with autophagy is a crucial step towards a deeper understanding of its role in these diseases. Methods for monitoring autophagy include TEM, Western blot, immunofluorescence, flow cytometry, and genetic tools. Autophagosome and autolysosome structures are discerned via TEM. Western blot, immunofluorescence, northern blot, and RT-PCR assess protein/mRNA levels. Luciferase assay tracks flux; GFP-LC3 transgenic mice aid study. Knockdown methods (miRNA and RNAi) offer insights. This article extensively examines autophagy's molecular mechanism, pharmacological regulation, and therapeutic application involvement in urological diseases.
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Affiliation(s)
- Kuang-Shun Chueh
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, San-min District, Kaohsiung 80708, Taiwan;
- Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Jian-He Lu
- Center for Agricultural, Forestry, Fishery, Livestock and Aquaculture Carbon Emission Inventory and Emerging Compounds (CAFEC), General Research Service Center, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
| | - Tai-Jui Juan
- Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan;
- Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Shu-Mien Chuang
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Yung-Shun Juan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, San-min District, Kaohsiung 80708, Taiwan;
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
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Diani E, Lagni A, Lotti V, Tonon E, Cecchetto R, Gibellini D. Vector-Transmitted Flaviviruses: An Antiviral Molecules Overview. Microorganisms 2023; 11:2427. [PMID: 37894085 PMCID: PMC10608811 DOI: 10.3390/microorganisms11102427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
Flaviviruses cause numerous pathologies in humans across a broad clinical spectrum with potentially severe clinical manifestations, including hemorrhagic and neurological disorders. Among human flaviviruses, some viral proteins show high conservation and are good candidates as targets for drug design. From an epidemiological point of view, flaviviruses cause more than 400 million cases of infection worldwide each year. In particular, the Yellow Fever, dengue, West Nile, and Zika viruses have high morbidity and mortality-about an estimated 20,000 deaths per year. As they depend on human vectors, they have expanded their geographical range in recent years due to altered climatic and social conditions. Despite these epidemiological and clinical premises, there are limited antiviral treatments for these infections. In this review, we describe the major compounds that are currently under evaluation for the treatment of flavivirus infections and the challenges faced during clinical trials, outlining their mechanisms of action in order to present an overview of ongoing studies. According to our review, the absence of approved antivirals for flaviviruses led to in vitro and in vivo experiments aimed at identifying compounds that can interfere with one or more viral cycle steps. Still, the currently unavailability of approved antivirals poses a significant public health issue.
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Affiliation(s)
- Erica Diani
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
| | - Anna Lagni
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
| | - Virginia Lotti
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
| | - Emil Tonon
- Unit of Microbiology, Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy;
| | - Riccardo Cecchetto
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
- Unit of Microbiology, Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy;
| | - Davide Gibellini
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
- Unit of Microbiology, Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy;
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Li C, Zhang Y, Zhao X, Li L, Kong X. Autophagy regulation of virus infection in aquatic animals. REVIEWS IN AQUACULTURE 2023; 15:1405-1420. [DOI: 10.1111/raq.12785] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 01/04/2023] [Indexed: 01/04/2025]
Abstract
AbstractAutophagy is a conserved intracellular degradation process that is required to maintain host homeostasis and cope with invading pathogens. Over the past few decades, studies on mammals have greatly increased our understanding of the relationship between autophagy and virus infection. Autophagy may convey the invader to lysosomes to degrade or activate the host immune response against virus replication. However, many viruses have developed some strategies that evade the degradative nature of autophagy or hijack this pathway for their gain. It follows that autophagy during viral infection is a double‐edged sword. In contrast to mammals, the review on autophagy modulated by the aquatic animal virus is limited. Here, after a brief description of the main information about autophagy, we highlight current progress on the interplays between autophagy and virus infection in aquatic animals, including the phenomenon of autophagy upon virus infection, the effect of modulating autophagy on virus replication, and the crosstalk between autophagy and immune response during virus infection. This review will help us better understand the pathogenic mechanism of aquatic animal viruses and develop proper antiviral countermeasures aimed at modulating autophagy.
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Affiliation(s)
- Chen Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Yunli Zhang
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Xianliang Zhao
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Li Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Xianghui Kong
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
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Chaaya C, Zgheib G, El Karak F. Pharmacotherapy developments in autophagy inhibitors for bladder cancer. Expert Opin Pharmacother 2023; 24:1853-1860. [PMID: 37668151 DOI: 10.1080/14656566.2023.2254697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 08/22/2023] [Accepted: 08/30/2023] [Indexed: 09/06/2023]
Abstract
INTRODUCTION Autophagy is an intracellular process that plays a key role in the cellular homeostasis. Recently, it has been described as a potential therapeutic target in oncology, whether by activating or inhibiting its different cascades. Autophagy inhibitors interact with different molecular processes of the hallmarks of cancer. AREAS COVERED Multiple proteins of the autophagy cascade could be aimed by specific inhibitors in many tumors, notably bladder cancer. In fact, bladder cancer has been increasing in prevalence over the last decade, and resistance to conventional treatment has been extensively reported in the literature. Autophagy inhibitors in bladder cancer have been described in preclinical studies to increase the sensitivity of the tumor to chemotherapy and radiotherapy. This paper is a review of the literature, which selected randomized trials, cohort studies, and case-control studies documenting the relationship between autophagy inhibitors and bladder cancer treatment. EXPERT OPINION Autophagy is a promising pathway for cancer cell targeting that opens the horizons for a potential new therapeutic area in particular the multidisciplinary management of bladder cancer.
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Affiliation(s)
- Celine Chaaya
- Department of Hematology and Oncology, Hotel-Dieu De France, Beirut, Lebanon
- Department of Hematology and Oncology, Saint Joseph University, Beirut, Lebanon
| | - Ghady Zgheib
- Department of Hematology and Oncology, Hotel-Dieu De France, Beirut, Lebanon
- Department of Hematology and Oncology, Saint Joseph University, Beirut, Lebanon
| | - Fadi El Karak
- Department of Hematology and Oncology, Hotel-Dieu De France, Beirut, Lebanon
- Department of Hematology and Oncology, Saint Joseph University, Beirut, Lebanon
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Smith M, Meliopoulos V, Tan S, Bub T, Brigleb PH, Sharp B, Crawford JC, Prater MS, Pruett-Miller SM, Schultz-Cherry S. The β6 Integrin Negatively Regulates TLR7-Mediated Epithelial Immunity via Autophagy During Influenza A Virus Infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.28.555098. [PMID: 37693589 PMCID: PMC10491108 DOI: 10.1101/2023.08.28.555098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Integrins are essential surface receptors that sense extracellular changes to initiate various intracellular signaling cascades. The rapid activation of the epithelial-intrinsic β6 integrin during influenza A virus (IAV) infection has been linked to innate immune impairments. Yet, how β6 regulates epithelial immunity remains undefined. Here, we identify the role of β6 in mediating the Toll-like receptor 7 (TLR7) through the regulation of intracellular trafficking. We demonstrate that deletion of the β6 integrin in lung epithelial cells significantly enhances the TLR7-mediated activation of the type I interferon (IFN) response during homeostasis and respiratory infection. IAV-induced β6 facilitates TLR7 trafficking to lysosome-associated membrane protein (LAMP2a) components, leading to a reduction in endosomal compartments and associated TLR7 signaling. Our findings reveal an unappreciated role of β6-induced autophagy in influencing epithelial immune responses during influenza virus infection.
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Shen J, Ma M, Duan W, Huang Y, Shi B, Wu Q, Wei X. Autophagy Alters the Susceptibility of Candida albicans Biofilms to Antifungal Agents. Microorganisms 2023; 11:2015. [PMID: 37630575 PMCID: PMC10458732 DOI: 10.3390/microorganisms11082015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Candida albicans (C. albicans) reigns as a major cause of clinical candidiasis. C. albicans biofilms are known to increase resistance to antifungal agents, making biofilm-related infections particularly challenging to treat. Drug resistance is of particular concern due to the spread of multidrug-resistant fungal pathogens, while autophagy is crucial for the maintenance of cellular homeostasis. Therefore, this study aimed to investigate the effects of an activator and an inhibitor of autophagy on the susceptibility of C. albicans biofilms to antifungal agents and the related mechanisms. The susceptibility of C. albicans biofilms to different antifungal agents after treatment with or without the autophagy activator or inhibitor was evaluated using XTT assay. Alkaline phosphatase (ALP) activity and reactive oxygen species (ROS) level, as well as the expression of ROS-related and autophagy-related genes, were examined to evaluate the autophagic activity of C. albicans biofilms when treated with antifungal agents. The autophagosomes were observed by transmission electron microscopy (TEM). The susceptibility of C. albicans biofilms to antifungal agents changed when autophagy changed. The ALP activity and ROS level of C. albicans biofilms increased with the treatment of antifungal agents, and autophagosomes could be observed in C. albicans biofilms. Autophagy was involved in the susceptibility of C. albicans biofilms to antifungal agents.
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Affiliation(s)
- Jiadi Shen
- Department of Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210000, China; (J.S.)
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210000, China
| | - Ming Ma
- Department of Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210000, China; (J.S.)
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210000, China
| | - Wei Duan
- Department of Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210000, China; (J.S.)
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210000, China
| | - Yun Huang
- Department of Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210000, China; (J.S.)
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210000, China
| | - Banruo Shi
- Department of Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210000, China; (J.S.)
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210000, China
| | - Qiaochu Wu
- Department of Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210000, China; (J.S.)
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210000, China
| | - Xin Wei
- Department of Endodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210000, China; (J.S.)
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210000, China
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Nuta GC, Gilad Y, Goldberg N, Meril S, Bahlsen M, Carvalho S, Kozer N, Barr H, Fridmann Sirkis Y, Hercík K, Břehová P, Nencka R, Bialik S, Eisenstein M, Kimchi A. Identifying a selective inhibitor of autophagy that targets ATG12-ATG3 protein-protein interaction. Autophagy 2023; 19:2372-2385. [PMID: 37184247 PMCID: PMC10351452 DOI: 10.1080/15548627.2023.2178159] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/24/2023] Open
Abstract
Macroautophagy/autophagy is a catabolic process by which cytosolic content is engulfed, degraded and recycled. It has been implicated as a critical pathway in advanced stages of cancer, as it maintains tumor cell homeostasis and continuous growth by nourishing hypoxic or nutrient-starved tumors. Autophagy also supports alternative cellular trafficking pathways, providing a mechanism of non-canonical secretion of inflammatory cytokines. This opens a significant therapeutic opportunity for using autophagy inhibitors in cancer and acute inflammatory responses. Here we developed a high throughput compound screen to identify inhibitors of protein-protein interaction (PPI) in autophagy, based on the protein-fragment complementation assay (PCA). We chose to target the ATG12-ATG3 PPI, as this interaction is indispensable for autophagosome formation, and the analyzed structure of the interaction interface predicts that it may be amenable to inhibition by small molecules. We screened 41,161 compounds yielding 17 compounds that effectively inhibit the ATG12-ATG3 interaction in the PCA platform, and which were subsequently filtered by their ability to inhibit autophagosome formation in viable cells. We describe a lead compound (#189) that inhibited GFP-fused MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta) puncta formation in cells with IC50 value corresponding to 9.3 μM. This compound displayed a selective inhibitory effect on the growth of autophagy addicted tumor cells and inhibited secretion of IL1B/IL-1β (interleukin 1 beta) by macrophage-like cells. Compound 189 has the potential to be developed into a therapeutic drug and its discovery documents the power of targeting PPIs for acquiring specific and selective compound inhibitors of autophagy.Abbreviations: ANOVA: analysis of variance; ATG: autophagy related; CQ: chloroquine; GFP: green fluorescent protein; GLuc: Gaussia Luciferase; HEK: human embryonic kidney; IL1B: interleukin 1 beta; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; PCA: protein-fragment complementation assay; PDAC: pancreatic ductal adenocarcinoma; PMA: phorbol 12-myristate 13-acetate; PPI: protein-protein interaction. VCL: vinculin.
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Affiliation(s)
- Gal Chaim Nuta
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Yuval Gilad
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Nadav Goldberg
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Sara Meril
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Marcela Bahlsen
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Silvia Carvalho
- The Nancy and Stephen Grand Israel National Center for Personalized Medicine (G-INCPM), Weizmann Institute of Science, Rehovot, Israel
| | - Noga Kozer
- The Nancy and Stephen Grand Israel National Center for Personalized Medicine (G-INCPM), Weizmann Institute of Science, Rehovot, Israel
| | - Haim Barr
- The Nancy and Stephen Grand Israel National Center for Personalized Medicine (G-INCPM), Weizmann Institute of Science, Rehovot, Israel
| | - Yael Fridmann Sirkis
- Department of Life Science Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Kamil Hercík
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Petra Břehová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Radim Nencka
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Shani Bialik
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Miriam Eisenstein
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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Zsiros V, Dóczi N, Petővári G, Pop A, Erdei Z, Sebestyén A, L Kiss A. BMP-induced non-canonical signaling is upregulated during autophagy-mediated regeneration in inflamed mesothelial cells. Sci Rep 2023; 13:10426. [PMID: 37369758 PMCID: PMC10300029 DOI: 10.1038/s41598-023-37453-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 06/22/2023] [Indexed: 06/29/2023] Open
Abstract
Previously, we showed that after Freund's adjuvant-induced peritonitis, rat mesothelial cells regain their epithelial phenotype through mesenchymal-epithelial transition (MET) accompanied by autophagy. Since bone morphogenetic proteins (BMPs) are well-known MET-inducers, we were interested in the potential expression of BMPs and BMP-induced pathways. Although mesothelial cells expressed lower amounts of BMP7, its level in the peritoneal cavity and mesothelial synthesis of BMP4 were significantly increased during inflammation. BMPR1A and BMPR2 were also significantly expressed. Expression of transforming growth factor beta-activated kinase (TAK1) and c-Jun NH2-terminal kinases (JNK1-JNK2) were more intense than that of phosphorylated Mothers Against Decapentaplegic homolog 1/5 (p-SMAD1/5), confirming that the non-canonical pathway of BMPs prevailed in our model. JNK signaling through B-cell lymphoma-2 (Bcl-2) can contribute to Beclin-1 activation. We demonstrated that TAK1-JNK-Bcl-2 signaling was upregulated simultaneously with the autophagy-mediated regeneration. A further goal of our study was to prove the regenerative role of autophagy after inflammation. We used a specific inhibitor, bafilomycin A1 (BafA1), and found that BafA1 treatment decreased the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3B) and resulted in morphological signs of cell death in inflamed mesothelial cells indicating that if autophagy is arrested, regeneration turns into cell death and consequently, mesothelial cells die.
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Affiliation(s)
- Viktória Zsiros
- Department of Anatomy, Histology and Embryology, Semmelweis University Budapest, Tűzoltó u. 58., Budapest, 1094, Hungary.
| | - Nikolett Dóczi
- Department of Anatomy, Histology and Embryology, Semmelweis University Budapest, Tűzoltó u. 58., Budapest, 1094, Hungary
| | - Gábor Petővári
- Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Üllői út 26., Budapest, 1085, Hungary
| | - Alexandra Pop
- Department of Anatomy, Histology and Embryology, Semmelweis University Budapest, Tűzoltó u. 58., Budapest, 1094, Hungary
| | - Zsófia Erdei
- Department of Anatomy, Histology and Embryology, Semmelweis University Budapest, Tűzoltó u. 58., Budapest, 1094, Hungary
| | - Anna Sebestyén
- Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Üllői út 26., Budapest, 1085, Hungary
| | - Anna L Kiss
- Department of Anatomy, Histology and Embryology, Semmelweis University Budapest, Tűzoltó u. 58., Budapest, 1094, Hungary
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Sánchez-Vidaña DI, Li J, Abokyi S, Chan JNM, Ngai SPC, Lau BWM. In vitro methods in autophagy research: Applications in neurodegenerative diseases and mood disorders. Front Mol Neurosci 2023; 16:1168948. [PMID: 37122628 PMCID: PMC10130388 DOI: 10.3389/fnmol.2023.1168948] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 03/14/2023] [Indexed: 05/02/2023] Open
Abstract
Background Autophagy is a conserved physiological intracellular mechanism responsible for the degradation and recycling of cytoplasmic constituents (e.g., damaged organelles, and protein aggregates) to maintain cell homeostasis. Aberrant autophagy has been observed in neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD), and recently aberrant autophagy has been associated with mood disorders, such as depression. Several in vitro methods have been developed to study the complex and tightly regulated mechanisms of autophagy. In vitro methods applied to autophagy research are used to identify molecular key players involved in dysfunctional autophagy and to screen autophagy regulators with therapeutic applications in neurological diseases and mood disorders. Therefore, the aims of this narrative review are (1) to compile information on the cell-based methods used in autophagy research, (2) to discuss their application, and (3) to create a catalog of traditional and novel in vitro methods applied in neurodegenerative diseases and depression. Methods Pubmed and Google Scholar were used to retrieve relevant in vitro studies on autophagy mechanisms in neurological diseases and depression using a combination of search terms per mechanism and disease (e.g., "macroautophagy" and "Alzheimer's disease"). A total of 37 studies were included (14 in PD, 8 in AD, 5 in ALS, 5 in %, and 5 in depression). Results A repertoire of traditional and novel approaches and techniques was compiled and discussed. The methods used in autophagy research focused on the mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy. The in vitro tools presented in this review can be applied to explore pathophysiological mechanisms at a molecular level and to screen for potential therapeutic agents and their mechanism of action, which can be of great importance to understanding disease biology and potential therapeutic options in the context of neurodegenerative disorders and depression. Conclusion This is the first review to compile, discuss, and provide a catalog of traditional and novel in vitro models applied to neurodegenerative disorders and depression.
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Affiliation(s)
- Dalinda Isabel Sánchez-Vidaña
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
- Mental Health Research Centre, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Jingjing Li
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Samuel Abokyi
- School of Optometry, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Jackie Ngai-Man Chan
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Shirley Pui-Ching Ngai
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Benson Wui-Man Lau
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
- Mental Health Research Centre, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
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López-Méndez TB, Sánchez-Álvarez M, Trionfetti F, Pedraz JL, Tripodi M, Cordani M, Strippoli R, González-Valdivieso J. Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective. Cell Biosci 2023; 13:44. [PMID: 36871010 PMCID: PMC9985235 DOI: 10.1186/s13578-023-00986-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 02/10/2023] [Indexed: 03/06/2023] Open
Abstract
In recent years, progress in nanotechnology provided new tools to treat cancer more effectively. Advances in biomaterials tailored for drug delivery have the potential to overcome the limited selectivity and side effects frequently associated with traditional therapeutic agents. While autophagy is pivotal in determining cell fate and adaptation to different challenges, and despite the fact that it is frequently dysregulated in cancer, antitumor therapeutic strategies leveraging on or targeting this process are scarce. This is due to many reasons, including the very contextual effects of autophagy in cancer, low bioavailability and non-targeted delivery of existing autophagy modulatory compounds. Conjugating the versatile characteristics of nanoparticles with autophagy modulators may render these drugs safer and more effective for cancer treatment. Here, we review current standing questions on the biology of autophagy in tumor progression, and precursory studies and the state-of-the-art in harnessing nanomaterials science to enhance the specificity and therapeutic potential of autophagy modulators.
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Affiliation(s)
- Tania B López-Méndez
- NanoBioCel Group, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.,Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Miguel Sánchez-Álvarez
- Area of Cell and Developmental Biology. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.,Instituto de Investigaciones Biomédicas Alberto Sols (IIB), Madrid, Spain
| | - Flavia Trionfetti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.,National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy
| | - José L Pedraz
- NanoBioCel Group, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.,Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Marco Tripodi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.,National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, Madrid, Spain. .,Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. .,National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy.
| | - Juan González-Valdivieso
- Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, USA.
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Tang SC, Lu CT, Ko JL, Lin CH, Hsiao YP. Hydroxychloroquine repairs burn damage through the Wnt/β-catenin pathway. Chem Biol Interact 2023; 370:110309. [PMID: 36535310 DOI: 10.1016/j.cbi.2022.110309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/22/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Affiliation(s)
- Sheau-Chung Tang
- Department of Nursing, National Taichung University of Science and Technology, Taichung, 40640, Taiwan
| | - Chun-Te Lu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jiunn-Liang Ko
- Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan; Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Cheng-Hui Lin
- Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Ping Hsiao
- Department of Dermatology, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
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Aparicio IM, Rojo-Domínguez P, Castillejo-Rufo A, Peña FJ, Tapia JA. The Autophagy Marker LC3 Is Processed during the Sperm Capacitation and the Acrosome Reaction and Translocates to the Acrosome Where It Colocalizes with the Acrosomal Membranes in Horse Spermatozoa. Int J Mol Sci 2023; 24:ijms24020937. [PMID: 36674454 PMCID: PMC9862423 DOI: 10.3390/ijms24020937] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/25/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
Despite its importance in somatic cells and during spermatogenesis, little is known about the role that autophagy may play in ejaculated spermatozoa. Our aim was to investigate whether the molecular components of autophagy, such as microtubule-associated protein 1 light chain 3 (LC3), are activated in stallion spermatozoa during the capacitation and acrosome reaction and if this activation could modulate these biological processes. To analyze the autophagy turnover, LC3I and LC3II proteins were assessed by western blotting, and the ratio between both proteins (LC3II/LC3I) was calculated. In somatic cells, this ratio indicates that autophagy has been activated and similar LC3 processing has been described in mammalian spermatozoa. The subcellular localization of autophagy-related proteins was assessed by immunofluorescence with specific antibodies that recognized Atg16, Beclin-1, and LC3. The colocalization of acrosomal membranes (PNA) and LC3 was studied by confocal microcopy, and the acrosome reacted cells were quantified by flow cytometry. The incubation of stallion sperm in capacitating conditions (BWW; 3 h) significantly increased LC3 processing. This increment was three to four times higher after the induction of the acrosome reaction in these cells. LC3 was mainly expressed in the head in mature ejaculated sperm showing a clear redistribution from the post-acrosomal region to the acrosome upon the incubation of sperm in capacitating conditions (BWW, 3 h). After the induction of the acrosome reaction, LC3 colocalized with the acrosome or the apical plasmalemma membranes in the head of the stallion spermatozoa. The inhibition or activation of autophagy-related pathways in the presence of autophagy activators (STF-62247) or inhibitors (E-64d, chloroquine) significantly increased LC3 processing and increased the percent of acrosome reacted cells, whereas 3-methyladenine almost completely inhibited LC3 processing and the acrosome reaction. In conclusion, we found that sperm capacitation and acrosome reaction could be regulated by autophagy components in sperm cells ex vivo by processes that might be independent of the intraluminal pH of the acrosome and dependent of LC3 lipidation. It can be speculated that, in stallion sperm, a form of noncanonical autophagy utilizes some components of autophagy machinery to facilitate the acrosome reaction.
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Affiliation(s)
- Ines M. Aparicio
- Department of Physiology, Institute of Molecular Pathology Biomarkers (BICOMCEL), University of Extremadura, 10003 Cáceres, Spain
| | - Patricia Rojo-Domínguez
- Laboratory of Spermatology, Veterinary Teaching Hospital, University of Extremadura, 10003 Cáceres, Spain
| | - Alba Castillejo-Rufo
- Department of Physiology, Institute of Molecular Pathology Biomarkers (BICOMCEL), University of Extremadura, 10003 Cáceres, Spain
| | - Fernando J. Peña
- Laboratory of Spermatology, Veterinary Teaching Hospital, University of Extremadura, 10003 Cáceres, Spain
| | - Jose A. Tapia
- Department of Physiology, Institute of Molecular Pathology Biomarkers (BICOMCEL), University of Extremadura, 10003 Cáceres, Spain
- Correspondence:
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