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Fu R, Hu R, Li W, Lv X, Zhao H, Li F. Unveiling drug resistance pathways in high-grade serous ovarian cancer(HGSOC): recent advances and future perspectives. Front Immunol 2025; 16:1556377. [PMID: 40370464 PMCID: PMC12075240 DOI: 10.3389/fimmu.2025.1556377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 04/14/2025] [Indexed: 05/16/2025] Open
Abstract
High-Grade Serous Ovarian Carcinoma (HGSOC) represents the most prevalent and lethal subtype of ovarian cancer, with approximately 225,000 new cases reported globally each year and a five-year survival rate of merely 49.1%. The clinical management of HGSOC encounters substantial challenges, primarily attributable to its intricate drug resistance mechanisms, which involve multiple biological processes, including tumor cell heterogeneity, microenvironment remodeling, gene mutations, and drug efflux. This study systematically reviews the most recent advancements in HGSOC drug resistance research, concentrating on the molecular biological foundations of resistance mechanisms, innovative detection strategies, and potential therapeutic approaches. The research indicates that HGSOC drug resistance constitutes a complex process characterized by multifactorial interactions, involving aberrant cell signaling pathways, dynamic alterations in the tumor microenvironment, and specific expressions of molecular markers. In this review, we systematically analyzed and investigated the intricate biological behaviors associated with HGSOC drug resistance, which not only enhances the understanding of disease progression but also provides essential theoretical foundations for the development of more precise and effective targeted therapies. This review firstly illustrated the detailed drug resistance cellular and molecular mechanisms underlying HGSOC chemotherapy, which can pave the way for future studies in HGSOC drug resistance practices.
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Affiliation(s)
- Ruiting Fu
- Gynaecology department of The First Affiliated Hospital, Shihezi University, Shihezi, Xinjiang, China
| | - Ruiyue Hu
- Gynaecology department, The People’s Hospital, Shihezi University, Shihezi, Xinjiang, China
| | - Wenting Li
- Gynaecology department of The First Affiliated Hospital, Shihezi University, Shihezi, Xinjiang, China
| | - Xifang Lv
- Gynaecology department of The First Affiliated Hospital, Shihezi University, Shihezi, Xinjiang, China
| | - Hanwei Zhao
- Peripheral vascular disease department of The First Affiliated Hospital, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China
| | - Fuxia Li
- Gynaecology department of The First Affiliated Hospital, Shihezi University, Shihezi, Xinjiang, China
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Yuan Z, Lin B, Wang C, Yan Z, Yang F, Su H. Collagen remodeling-mediated signaling pathways and their impact on tumor therapy. J Biol Chem 2025; 301:108330. [PMID: 39984051 PMCID: PMC11957794 DOI: 10.1016/j.jbc.2025.108330] [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: 08/27/2024] [Revised: 01/28/2025] [Accepted: 02/05/2025] [Indexed: 02/23/2025] Open
Abstract
In addition to their traditional roles in maintaining tissue morphology and organ development, emerging evidence suggests that collagen (COL) remodeling-referring to dynamic changes in the quantity, stiffness, arrangements, cleavage states, and homo-/hetero-trimerization of COLs-serves as a key signaling mechanism that governs tumor growth and metastasis. COL receptors act as switches, linking various forms of COL remodeling to different cell types during cancer progression, including cancer cells, immune cells, and cancer-associated fibroblasts. In this review, we summarize recent findings on the signaling pathways mediated by COL arrangement, cleavage, and trimerization states (both homo- and hetero-), as well as the roles of the primary COL receptors-integrin, DDR1/2, LAIR-1/2, MRC2, and GPVI-in cancer progression. We also discuss the latest therapeutic strategies targeting COL fragments, cancer-associated fibroblasts, and COL receptors, including integrins, DDR1/2, and LAIR1/2. Understanding the pathways modulated by COL remodeling and COL receptors in various pathological contexts will pave the way for developing new precision therapies.
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Affiliation(s)
- Zihang Yuan
- Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Bo Lin
- Liver Cancer Institute, Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chunlan Wang
- Liver Cancer Institute, Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Zhaoyue Yan
- The Department of Stomatology, Shandong Public Health Clinical Center, Shandong University, Jinan, Shandong, China
| | - Fei Yang
- Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Hua Su
- Liver Cancer Institute, Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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He J, He M, Sun M, Chen H, Dou Z, Nie R, Zhou J, Tang Q, Che C, Liu J, Li T. The Mechanism of Acupuncture Regulating Autophagy: Progress and Prospect. Biomolecules 2025; 15:263. [PMID: 40001566 PMCID: PMC11852493 DOI: 10.3390/biom15020263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/08/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Autophagy plays a crucial role in the physiopathological mechanisms of diseases by regulating cellular functions and maintaining cellular homeostasis, which has garnered extensive attention from researchers worldwide. The holistic regulation and bidirectional regulation effects of acupuncture can modulate cellular autophagy, promoting or restoring the homeostasis of the body's internal environment to achieve therapeutic outcomes. This paper systematically reviews the research progress on the use of acupuncture for treating various diseases via the autophagy pathway, summarizes signal pathways related to acupuncture regulating autophagy, and analyzes the deficiencies present in the existing research. The review results indicate that the mechanism of action of acupuncture on autophagy dysfunction is reflected in the changes in LC3, Beclin1, p53, and autophagy-associated (ATG) protein expression, and regulates signaling pathways and key proteins or genes. The regulatory effect of acupuncture on autophagy capacity is bidirectional: it inhibits the abnormal activation of autophagy to prevent exacerbation of injury and reduce apoptosis, while also activating or enhancing autophagy to promote the elimination of inflammation and reduce oxidative stress. Further analysis suggests that the mechanisms of acupuncture regulating autophagy are insufficiently explored. Future research should prioritize the development of more appropriate animal models, analyzing the accuracy of relevant pathways and the specificity of indicators, exploring the synergistic effects among targets and signaling pathways, clarifying the regulatory mechanisms of acupuncture at various stages of autophagy, and evaluating the efficacy of acupuncture in autophagy modulating. This paper offers valuable insights into the regulation of autophagy by acupuncture.
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Affiliation(s)
- Jing He
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China; (J.H.); (H.C.); (Z.D.); (R.N.); (Q.T.); (C.C.)
| | - Min He
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China;
| | - Mengmeng Sun
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China;
| | - Hongxiu Chen
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China; (J.H.); (H.C.); (Z.D.); (R.N.); (Q.T.); (C.C.)
| | - Zhiqiang Dou
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China; (J.H.); (H.C.); (Z.D.); (R.N.); (Q.T.); (C.C.)
| | - Ru Nie
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China; (J.H.); (H.C.); (Z.D.); (R.N.); (Q.T.); (C.C.)
| | - Jun Zhou
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China;
| | - Qingqing Tang
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China; (J.H.); (H.C.); (Z.D.); (R.N.); (Q.T.); (C.C.)
| | - Cong Che
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China; (J.H.); (H.C.); (Z.D.); (R.N.); (Q.T.); (C.C.)
| | - Jie Liu
- Academic Affairs Office, Changchun University of Chinese Medicine, Changchun 130117, China;
| | - Tie Li
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China; (J.H.); (H.C.); (Z.D.); (R.N.); (Q.T.); (C.C.)
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Zhang J, Zhang J, Yang C. Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities. J Transl Med 2025; 23:52. [PMID: 39806481 PMCID: PMC11727735 DOI: 10.1186/s12967-024-06063-0] [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: 07/20/2024] [Accepted: 12/27/2024] [Indexed: 01/16/2025] Open
Abstract
Autophagy is responsible for maintaining cellular balance and ensuring survival. Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. However, brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. Hence, having knowledge of the role of molecular processes in the advancement of brain tumors is enlightening, and the current review specifically examines the role of autophagy. The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation. Autophagy can inhibit the growth of brain tumors by promoting apoptosis. Hence, focusing on autophagy could offer fresh perspectives on creating successful treatments.
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Affiliation(s)
- Jiarui Zhang
- Department of Pathology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jinan Zhang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, China.
| | - Chen Yang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, China.
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Xia Q, Zhang J. Interaction Between Autophagy and the Inflammasome in Human Tumors: Implications for the Treatment of Human Cancers. Cell Biochem Funct 2025; 43:e70035. [PMID: 39722223 DOI: 10.1002/cbf.70035] [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: 09/27/2024] [Revised: 10/10/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024]
Abstract
Autophagy is a physiologically regulated cellular process orchestrated by autophagy-related genes (ATGs) that, depending on the tumor type and stage, can either promote or suppress tumor growth and progression. It can also modulate cancer stem cell maintenance and immune responses. Therefore, targeted manipulation of autophagy may inhibit tumor development by overcoming tumor-promoting mechanisms. The inflammasome is another multifunctional bioprocess that induces a form of pro-inflammatory programmed cell death, called pyroptosis. Dysregulation or overactivation of the inflammasome has been implicated in tumor pathogenesis and development. Additionally, autophagy can inhibit the NLRP3 inflammasome by removing inflammatory drivers. Recent research suggests that the NLRP3 inflammasome, in turn, affects autophagy. Understanding the complex interplay between autophagy and inflammasomes could lead to more precise and effective strategies for cancer treatments. In this review, we summarize the impact of autophagy and inflammasome dysregulation on tumor progression or suppression. We then highlight their targeting for cancer treatment as monotherapy or in combination with other therapies. Furthermore, we discuss the interaction between autophagy and tumor-promoting inflammation or the NLRP3 inflammasome. Finally, based on recent findings, we review the potential of this interaction for cancer treatment.
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Affiliation(s)
- Qing Xia
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingzhou Zhang
- Peking Union Medical College, Graduate School of Peking Union Medical College, Beijing, China
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Wang ZQ, Wu ZX, Chen JW, Li HF, Wu HD, Bao JX, Cheng Y, Dai YW, Wang OC, Dai XX. Cyclovirobuxine D inhibits triple-negative breast cancer via YAP/TAZ suppression and activation of the FOXO3a/PINK1-Parkin pathway-induced mitophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156287. [PMID: 39615216 DOI: 10.1016/j.phymed.2024.156287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 10/31/2024] [Accepted: 11/21/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is characterized by its rapid progression and aggressive nature, with limited effective therapeutic interventions currently available. Cyclovirobuxine D (CVB-D), a natural alkaloid extracted from the traditional Chinese herb Buxus sinica, is renowned for its cardioprotective and anti-ischemic effects, demonstrating notable anti-cancer properties. Nevertheless, the anti-tumor effects of CVB-D on TNBC remain unverified. PURPOSE This study seeks to investigate the effects of CVB-D on TNBC and to uncover the underlying mechanisms. STUDY DESIGN Network pharmacology, SPR, DSF, and cell-based functional assays were conducted on TNBC cells to assess the impact of CVB-D. Findings were further corroborated using xenograft mouse models. METHODS Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, transwell assays, flow cytometry, wound healing assays, immunofluorescence, and immunoblotting were employed to evaluate CVB-D's influence on TNBC cell lines. SPR, DSF and molecular docking techniques were utilized to assess the binding affinity of CVB-D to Yes-associated protein (YAP). The interaction between CVB-D and autophagy/mitophagy was further analyzed through plasmid transient transfection, JC-1 assay, TUNEL assay, and the use of autophagy inhibitors. The anti-TNBC mechanism of CVB-D was elucidated by overexpressing YAP in MDA-MB-231 cells. Additionally, the in vivo efficacy and safety of CVB-D were assessed in a xenograft mouse model. RESULTS In vitro analyses revealed that CVB-D effectively suppressed G1 phase arrest and inhibited TNBC cell proliferation. Moreover, CVB-D induced mitochondrial-dependent apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, CVB-D exerted its anti-cancer effects by directly binding to YAP, thereby inhibiting the nuclear translocation of YAP/TAZ and suppressing the transcription of downstream oncogenic target genes. Furthermore, CVB-D triggered excessive mitophagy by activating the FOXO3a/PINK1-Parkin axis, promoting apoptosis and leading to mitochondrial dysfunction in TNBC cells. Elevated YAP expression counteracted the effects of CVB-D on TNBC, including the suppression of mitophagy-related protein expression induced by CVB-D, suggesting that YAP modulates mitophagy through the FOXO3a/PINK1-Parkin axis. The anti-tumor efficacy of CVB-D and its underlying mechanisms were further substantiated using a subcutaneous xenograft model. CONCLUSIONS This study is the first to demonstrate that CVB-D can directly bind to the YAP target, proposing a novel therapeutic strategy for TNBC. CVB-D may serve both as a YAP/TAZ inhibitor and as an activator of the FOXO3a/PINK1-Parkin axis, leading to excessive mitophagy.
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Affiliation(s)
- Zi-Qiong Wang
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Zhi-Xuan Wu
- Department of Colorectal Surgery, Sir Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310016, PR China
| | - Jia-Wei Chen
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Hong-Feng Li
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Hao-Dong Wu
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Jing-Xia Bao
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Yao Cheng
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Yin-Wei Dai
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Ou-Chen Wang
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China; Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, PR China.
| | - Xuan-Xuan Dai
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China; Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, PR China.
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Li D, Jiang N, Pan M, Ma L, Huang Y, Xu X, Yang X, Zhu Y, Shi H, Zhao SC. OCTN2 expression and function in the Sertoli cells of testes from patients with non-obstructive azoospermia. J Mol Histol 2024; 56:31. [PMID: 39636482 DOI: 10.1007/s10735-024-10298-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: 09/20/2024] [Accepted: 10/16/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Among couples, male factors account for approximately 50% of infertility cases, with nonobstructive azoospermia (NOA) representing one of the most clinically common and severe categories of male infertility, affecting approximately 10-15% of patients. Currently, L-carnitine is clinically used to improve spermatogenesis by regulating Sertoli cell function. Multiple clinical trials have described the efficacy of L-carnitine in treating NOA. Notably, Sertoli cells rely on organic carnitine transporter 2 (OCTN2) for carnitine transport. However, it remains unknown whether OCTN2 expression is involved in the pathological process of NOA. OBJECTIVE To investigate the expression and function of OCTN2 in Sertoli cells from patients with NOA. MATERIALS AND METHODS Ten testicular tissue samples were collected, including five from a healthy group and five from a group of patients with NOA. Immunohistochemistry and immunofluorescence were used to detect the expression of OCTN2 in testicular tissue. Additionally, an Octn2-KO TM4 cell line (a mouse testicular Sertoli cell line) was constructed to explore the function of OCTN2 expression in Sertoli cells through transcriptomic sequencing, cell proliferation experiments, metabolomic analysis, and Western blot analysis. RESULTS Compared with those of the healthy group, the immunohistochemistry results revealed a significant decrease in OCTN2 expression in the Sertoli cells of the NOA group. Further investigation through cell proliferation experiments revealed a reduction in the proliferative capacity of the Octn2-KO TM4 cell line. Transcriptomic sequencing and metabolomic data analysis revealed a decrease in autophagy in the Octn2-KO TM4 cell line. Western blot analysis subsequently verified the expression levels of autophagy-related proteins. CONCLUSION In the Sertoli cells of NOA patients, decreased OCTN2 protein expression leads to decreased cell proliferation and autophagy abnormalities, which may play a crucial role in the spermatogenic dysfunction observed in NOA patients.
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Affiliation(s)
- Dong Li
- Department of Urology, Nanfang Hospital, Southern Medical University, No. 1023-1063 Shatai South Road, Baiyun District, Guangzhou, 510515, Guangdong, China
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Department of Urology, People's Hospital of Yingde City Guangdong Province, Yingde, Guangdong, China
| | - Nan Jiang
- Department of Urology, Nanfang Hospital, Southern Medical University, No. 1023-1063 Shatai South Road, Baiyun District, Guangzhou, 510515, Guangdong, China
| | - Minjia Pan
- Department of Urology, Nanfang Hospital, Southern Medical University, No. 1023-1063 Shatai South Road, Baiyun District, Guangzhou, 510515, Guangdong, China
| | - Linzi Ma
- Department of Gynecology and Obstetrics, Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yunchong Huang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoheng Xu
- Department of Clinical Laboratory, The Seventh Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, China
| | - Xinyan Yang
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yongtong Zhu
- Department of Gynecology and Obstetrics, Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hua Shi
- Department of Reproductive Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Shan-Chao Zhao
- Department of Urology, Nanfang Hospital, Southern Medical University, No. 1023-1063 Shatai South Road, Baiyun District, Guangzhou, 510515, Guangdong, China.
- Department of Urology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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Basilotta R, Casili G, Mannino D, Filippone A, Lanza M, Capra AP, Giosa D, Forte S, Colarossi L, Sciacca D, Esposito E, Paterniti I. Benzyl isothiocyanate suppresses development of thyroid carcinoma by regulating both autophagy and apoptosis pathway. iScience 2024; 27:110796. [PMID: 39398237 PMCID: PMC11471196 DOI: 10.1016/j.isci.2024.110796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/09/2024] [Accepted: 08/20/2024] [Indexed: 10/15/2024] Open
Abstract
Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, characterized by rapid growth and invasion and poor prognosis. Due to its rarity and aggressive nature, ATC is a difficult condition to treat, thus knowledge of the mechanisms underlying its progression represents important research challenges. Benzyl isothiocyanate (BITC) is a natural compound that has shown promising anticancer properties. The aim of this study was to evaluate the antitumor effect of BITC in ATC, highlighting signaling pathways involved in BITC mechanism of action. This work included in vitro and in vivo studies. Results obtained indicate that BITC, both in vitro and in vivo, has the potential to slow the progression of ATC through interactions with autophagy, reduction in epithelial-mesenchymal transition (EMT) and attenuation of inflammation. In conclusion, this study identifies BITC as a compound worth further investigation for the development of new treatment strategies for this aggressive form of thyroid cancer.
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Affiliation(s)
- Rossella Basilotta
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
| | - Giovanna Casili
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
| | - Deborah Mannino
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
| | - Alessia Filippone
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
| | - Marika Lanza
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
| | - Anna Paola Capra
- Department of Clinical and Experimental Medicine, University of Messina, Viale Ferdinando Stagno D' Alcontres 31, 98166 Messina, ME, Italy
| | - Domenico Giosa
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
| | - Stefano Forte
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, Italy
| | - Lorenzo Colarossi
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, Italy
| | - Dorotea Sciacca
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, Italy
| | - Emanuela Esposito
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
| | - Irene Paterniti
- Departement of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
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Mokarram P, Ghavami S. Autophagy unveiled: New horizons in health and disease. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167289. [PMID: 38871032 DOI: 10.1016/j.bbadis.2024.167289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Affiliation(s)
- Pooneh Mokarram
- Autophagy Research Center, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Ghavami
- Faculty of Medicine in Zabrze, University of Technology in Katowice, Zabrze, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, Canada; Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada; Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.
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10
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Li Z, Yu H, Hussain SA, Yang R. Anticancer activity of Araguspongine C via inducing apoptosis, and inhibition of oxidative stress, inflammation, and EGFR-TK in human lung cancer cells: An in vitro and in vivo study. J Biochem Mol Toxicol 2024; 38:e23763. [PMID: 38984790 DOI: 10.1002/jbt.23763] [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: 03/27/2024] [Revised: 06/18/2024] [Accepted: 06/24/2024] [Indexed: 07/11/2024]
Abstract
The advanced non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations has put a selective pressure on the discovery and development of newer EGFR inhibitors. Therefore, the present study intends to explore the pharmacological effect of Araguspongine C (Aragus-C) as anticancer agent against lung cancer. The effect of Aragus-C was evaluated on the viability of the A549 and H1975 cells. Further biochemical assays were performed to elaborate the effect of Aragus-C, on the apoptosis, cell-cycle analysis, and mitochondrial membrane potential in A549 cells. Western blot analysis was also conducted to determine the expression of EGFR in A549 cells. Tumor xenograft mice model from A549 cells was established to further elaborate the pharmacological activity of Aragus-C. Results suggest that Aragus C showed significant inhibitory activity against A549 cells as compared to H1975 cells. It has been found that Aragus-C causes the induction of apoptosis and promotes cell-cycle arrest at the G2/M phase of A549 cells. It also showed a reduction in the overexpression of EGFR in A549 cells. In tumor xenograft mice model, it showed a significant reduction of tumor volume in a dose-dependent manner, with maximum inhibitory activity was reported by the 8 mg/kg treated group. It also showed significant anti-inflammatory and antioxidant activity by reducing the level of TNF-α, IL-1β, IL-6, and MDA, with a simultaneous increase of superoxide dismutase and glutathione peroxidase. We have demonstrated the potent anti-lung cancer activity of Aragus-C, and it may be considered as a potential therapeutic choice for NSCLC treatment.
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Affiliation(s)
- Zhe Li
- Department of Oncology and Hematology, Yan'an People's Hospital, Yan'an, China
| | - Hongjiang Yu
- Department of Medical Oncology, Tongliao City Hospital, Tongliao, China
| | - Shaik Althaf Hussain
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Rui Yang
- Department of Medical Oncology, Yan'an People's Hospital, Yan'an, China
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11
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Esrefoglu M. Harnessing autophagy: A potential breakthrough in digestive disease treatment. World J Gastroenterol 2024; 30:3036-3043. [PMID: 38983959 PMCID: PMC11230060 DOI: 10.3748/wjg.v30.i24.3036] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/30/2024] [Accepted: 06/04/2024] [Indexed: 06/25/2024] Open
Abstract
Autophagy, a conserved cellular degradation process, is crucial for various cellular processes such as immune responses, inflammation, metabolic and oxidative stress adaptation, cell proliferation, development, and tissue repair and remodeling. Dysregulation of autophagy is suspected in numerous diseases, including cancer, neurodegenerative diseases, digestive disorders, metabolic syndromes, and infectious and inflammatory diseases. If autophagy is disrupted, for example, this can have serious consequences and lead to chronic inflammation and tissue damage, as occurs in diseases such as Chron's disease and ulcerative colitis. On the other hand, the influence of autophagy on the development and progression of cancer is not clear. Autophagy can both suppress and promote the progression and metastasis of cancer at various stages. From inflammatory bowel diseases to gastrointestinal cancer, researchers are discovering the intricate role of autophagy in maintaining gut health and its potential as a therapeutic target. Researchers should carefully consider the nature and progression of diseases such as cancer when trying to determine whether inhibiting or stimulating autophagy is likely to be beneficial. Multidisciplinary approaches that combine cutting-edge research with clinical expertise are key to unlocking the full therapeutic potential of autophagy in digestive diseases.
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Affiliation(s)
- Mukaddes Esrefoglu
- Department of Histology and Embryology, Bezmialem Vakif University Medical Faculty, Istanbul 34093, Türkiye
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12
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Li X, Wu T, Chen W, Zhang J, Jiang Y, Deng J, Long W, Qin X, Zhou Y. Andrographolide acts with dexamethasone to inhibit the growth of acute lymphoblastic leukemia CEM‑C1 cells via the regulation of the autophagy‑dependent PI3K/AKT/mTOR signaling pathway. Biomed Rep 2024; 20:43. [PMID: 38357243 PMCID: PMC10865295 DOI: 10.3892/br.2024.1731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 08/29/2023] [Indexed: 02/16/2024] Open
Abstract
Acute lymphoblastic leukemia (ALL) is one of the most common malignant tumor types of the circulatory system. Dexamethasone (DEX) acts on the glucocorticoid (GC) receptor (GR) and is a first-line chemotherapy drug for ALL. However, long-term or high-dose applications of the drug can not only cause adverse reactions, such as osteoporosis and high blood pressure, but can also cause downregulation of GR and lead to drug resistance. In the present study, reverse transcription-quantitative PCR, western blotting and LysoTracker Red staining were used to observe the effects of DEX and andrographolide (AND; a botanical with antitumorigenic properties) combined treatment. It was found that AND enhanced the sensitivity of CEM-C1 cells, a GC-resistant cell line, to DEX, and synergistically upregulated GR both at the transcriptional and post-transcriptional level with DEX. The combination of AND with DEX synergistically alkalized lysosomal lumen and downregulated the expression of autophagy-related genes Beclin1 and microtubule-associated 1 protein light chain 3 (LC3), thereby inhibiting autophagy. Knocking down LC3 expression enhanced GR expression, suggesting that GR was regulated by autophagy. Furthermore, compared with the monotherapy group (AND or DEX in isolation), AND interacted with DEX to activate the autophagy-dependent PI3K/AKT/mTOR signaling pathway by enhancing the phosphorylation of PI3K, AKT and mTOR, thereby decreasing GR degradation and increasing the sensitivity of cells to GCs. In conclusion, the present study demonstrated that AND exhibited a synergistic anti-ALL effect with DEX via upregulation of GR, which was orchestrated by the autophagy-related PI3K/AKT/mTOR signaling pathway. The results of the present study therefore provided novel research avenues and strategies for the treatment of ALL.
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Affiliation(s)
- Xiaowen Li
- Department of Clinical Pharmacy, College of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
| | - Tong Wu
- Department of Clinical Pharmacy, College of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
| | - Weihong Chen
- Department of Clinical Pharmacy, College of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
| | - Jiannan Zhang
- Department of Clinical Pharmacy, College of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
| | - Yanping Jiang
- Department of Clinical Medicine, College of Lingui Clinical Medicine, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
| | - Jianzhi Deng
- Guangxi Key Laboratory of Embedded Technology and Intelligent System, Guilin University of Technology, Guilin, Guangxi Zhuang Autonomous Region 541004, P.R. China
| | - Wenqing Long
- Department of Clinical Medicine, College of Lingui Clinical Medicine, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
| | - Xi Qin
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Yuehan Zhou
- Department of Clinical Pharmacy, College of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
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13
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Perucho-Jaimes L, Do J, Van Elgort A, Kaplan KB. Septins modulate the autophagy response after nutrient starvation. Mol Biol Cell 2024; 35:ar4. [PMID: 37910217 PMCID: PMC10881159 DOI: 10.1091/mbc.e22-11-0520] [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: 11/18/2022] [Revised: 09/19/2023] [Accepted: 10/16/2023] [Indexed: 11/03/2023] Open
Abstract
The pathways that induce macroautophagy (referred to as autophagy hereafter) in response to the stress of starvation are well conserved and essential under nutrient-limiting conditions. However, less is understood about the mechanisms that modulate the autophagy response. Here we present evidence that after induction of autophagy in budding yeast septin filaments rapidly assemble into discrete patches distributed along the cell cortex. These patches gradually mature over 12 h of nutrient deprivation to form extended structures around Atg9 membranes tethered at the cortical endoplasmic reticulum, a class of membranes that are limiting for autophagosome biogenesis. Loss of cortical septin structures alters the kinetics of autophagy activation and most dramatically extends the duration of the autophagy response. In wild-type cells, diffusion of Atg9 membranes at the cell cortex undergoes transient pauses that are dependent on septins, and septins at the bud neck block the diffusion of Atg9 membranes between mother and daughter cells. We conclude that septins reorganize at the cell cortex during autophagy to locally limit access of Atg9 membranes to autophagosome assembly sites, and thus modulate the autophagy response during nutrient deprivation.
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Affiliation(s)
- Luis Perucho-Jaimes
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616
| | - Jonathan Do
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616
| | - Alexandria Van Elgort
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616
| | - Kenneth B. Kaplan
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616
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14
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Gao M, Xiao H, Liang Y, Cai H, Guo X, Lin J, Zhuang S, Xu J, Ye S. The Hyperproliferation Mechanism of Cholesteatoma Based on Proteomics: SNCA Promotes Autophagy-Mediated Cell Proliferation Through the PI3K/AKT/CyclinD1 Signaling Pathway. Mol Cell Proteomics 2023; 22:100628. [PMID: 37532176 PMCID: PMC10495652 DOI: 10.1016/j.mcpro.2023.100628] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 07/19/2023] [Accepted: 07/30/2023] [Indexed: 08/04/2023] Open
Abstract
Cholesteatoma is a chronic inflammatory ear disease with abnormal keratinized epithelium proliferation and tissue damage. However, the mechanism of keratinized epithelium hyperproliferation in cholesteatoma remains unknown. Hence, our study sought to shed light on mechanisms affecting the pathology and development of cholesteatoma, which could help develop adjunctive treatments. To investigate molecular changes in cholesteatoma pathogenesis, we analyzed clinical cholesteatoma specimens and paired ear canal skin with mass spectrometry-based proteomics and bioinformatics. From our screen, alpha-synuclein (SNCA) was overexpressed in middle ear cholesteatoma and might be a key hub protein associated with inflammation, proliferation, and autophagy in cholesteatoma. SNCA was more sensitive to lipopolysaccharide-induced inflammation, and autophagy marker increase was accompanied by autophagy activation in middle ear cholesteatoma tissues. Overexpression of SNCA activated autophagy and promoted cell proliferation and migration, especially under lipopolysaccharide inflammatory stimulation. Moreover, inhibiting autophagy impaired SNCA-mediated keratinocyte proliferation and corresponded with inhibition of the PI3K/AKT/CyclinD1 pathways. Also, 740Y-P, a PI3K activator reversed the suppression of autophagy and PI3K signaling by siATG5 in SNCA-overexpressing cells, which restored proliferative activity. Besides, knockdown of SNCA in RHEK-1 and HaCaT cells or knockdown of PI3K in RHEK-1 and HaCaT cells overexpressing SNCA both resulted in attenuated cell proliferation. Our studies indicated that SNCA overexpression in cholesteatoma might maintain the proliferative ability of cholesteatoma keratinocytes by promoting autophagy under inflammatory conditions. This suggests that dual inhibition of SNCA and autophagy may be a promising new target for treating cholesteatoma.
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Affiliation(s)
- Miao Gao
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Heng Xiao
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yonglan Liang
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Huimin Cai
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xiaojing Guo
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jianwei Lin
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Suling Zhuang
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jianhua Xu
- Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China.
| | - Shengnan Ye
- Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
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15
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Zhang Y, Yan L, Wang Z, Li F, Lv J, Liu J, Liu X, Bao L, Zhang Y. Bibliometric Analysis of Global Research on Tumor Dormancy. Cancers (Basel) 2023; 15:3230. [PMID: 37370845 DOI: 10.3390/cancers15123230] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Tumor dormancy continues to be a research hotspot with numerous pressing problems that need to be solved. The goal of this study is to perform a bibliometric analysis of pertinent articles published in the twenty-first century. We concentrate on significant keywords, nations, authors, affiliations, journals, and literature in the field of tumor dormancy, which will help researchers to review the results that have been achieved and better understand the directions of future research. We retrieved research articles on tumor dormancy from the Web of Science Core Collection. This study made use of the visualization tools VOSviewer, CiteSpace, and Scimago Graphica, as visualization helps us to uncover the intrinsic connections between information. Research on tumor dormancy has been growing in the 21st century, especially from 2015 to the present. The United States is a leader in many aspects of this research area, such as in the number of publications, the number of partners, the most productive institutions, and the authors working in this field. Harvard University is the institution with the highest number of publications, and Aguirre-Ghiso, Julio A. is the author with the highest number of publications and citations. The keywords that emerged after 2017 were "early dissemination", "inhibition", "mechanism", "bone metastasis", and "promotion". We believe that research on tumor dormancy mechanisms and therapy has been, and will continue to be, a major area of interest. The exploration of the tumor dormancy microenvironment and immunotherapeutic treatments for tumor dormancy is likely to represent the most popular future research topics.
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Affiliation(s)
- Yuzhe Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
| | - Lirong Yan
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
| | - Zhongqing Wang
- Department of Information Center, The First Hospital of China Medical University, Shenyang 110001, China
| | - Fang Li
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
| | - Jinqi Lv
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
| | - Jiaqing Liu
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xuqin Liu
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
| | - Li Bao
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang 110001, China
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16
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Alhasan B, Mikeladze M, Guzhova I, Margulis B. Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence. Cancer Metastasis Rev 2023; 42:217-254. [PMID: 36723697 DOI: 10.1007/s10555-023-10085-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/16/2023] [Indexed: 02/02/2023]
Abstract
Tumor recurrence is a paradoxical function of a machinery, whereby a small proportion of the cancer cell population enters a resistant, dormant state, persists long-term in this condition, and then transitions to proliferation. The dormant phenotype is typical of cancer stem cells, tumor-initiating cells, disseminated tumor cells, and drug-tolerant persisters, which all demonstrate similar or even equivalent properties. Cancer cell dormancy and its conversion to repopulation are regulated by several protein signaling systems that inhibit or induce cell proliferation and provide optimal interrelations between cancer cells and their special niche; these systems act in close connection with tumor microenvironment and immune response mechanisms. During dormancy and reawakening periods, cell proteostasis machineries, autophagy, molecular chaperones, and the unfolded protein response are recruited to protect refractory tumor cells from a wide variety of stressors and therapeutic insults. Proteostasis mechanisms functionally or even physically interfere with the main regulators of tumor relapse, and the significance of these interactions and implications in the tumor recurrence phases are discussed in this review.
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Affiliation(s)
- Bashar Alhasan
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St. Petersburg, Russia.
| | - Marina Mikeladze
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St. Petersburg, Russia
| | - Irina Guzhova
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St. Petersburg, Russia
| | - Boris Margulis
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064, St. Petersburg, Russia
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17
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Li X, Liu S, Jin L, Ma Y, Liu T. NOD2 inhibits the proliferation of esophageal adenocarcinoma cells through autophagy. J Cancer Res Clin Oncol 2023; 149:639-652. [PMID: 36316517 PMCID: PMC9931811 DOI: 10.1007/s00432-022-04354-x] [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: 02/09/2022] [Accepted: 09/07/2022] [Indexed: 02/16/2023]
Abstract
AIM To study the regulatory mechanism of NOD2 in the inhibition of esophageal adenocarcinoma cell proliferation. METHODS Cell experiments: after confirming the decrease in NOD2 expression in esophageal adenocarcinoma, we overexpressed NOD2 in esophageal adenocarcinoma cells via lentivirus, compared and verified the changes in esophageal adenocarcinoma cell proliferation before and after NOD2 overexpression, and compared the overexpression group with the control group by mRNA sequencing to identify pathways that may affect cell proliferation. Then, the autophagy level of multiple groups were assessed, and the results were verified by rescue experiments. In vivo experiments: we administered esophageal adenocarcinoma cells to nude mice to form tumors under their skin and then injected the tumors with NOD2 overexpression lentivirus and negative control lentivirus. After a period of time, the growth curve of the tumor was generated, and the tumor was removed to generate sections. Ki67 was labeled with immunohistochemistry to verify cell proliferation, and the protein was extracted from the tissue to detect the molecular indices of the corresponding pathway. RESULTS Upregulation of NOD2 expression inhibited the proliferation of esophageal adenocarcinoma cells. Upregulation of NOD2 expression increased the autophagy level of esophageal adenocarcinoma cells via ATG16L1. After ATG16L1 was inhibited, NOD2 had no significant effect on autophagy and proliferation of esophageal adenocarcinoma cells. Enhanced autophagy in esophageal adenocarcinoma cell lines inhibited cell proliferation. In vivo, the upregulation of NOD2 expression improved the autophagy level of tumor tissue and inhibited cells proliferation. CONCLUSION NOD2 can activate autophagy in esophageal adenocarcinoma cells through the ATG16L1 pathway and inhibit cell proliferation.
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Affiliation(s)
- Xiaozhi Li
- Emergency Department, The Third XiangYa Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Suo Liu
- Cardiothoracic Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Longyu Jin
- Cardiothoracic Surgery, The Third XiangYa Hospital, Central South University, Changsha, 410013, Hunan, China.
| | - Yuchao Ma
- Cardiothoracic Surgery, The Third XiangYa Hospital, Central South University, Changsha, 410013, Hunan, China.
| | - Tao Liu
- Cardiothoracic Surgery, The Third XiangYa Hospital, Central South University, Changsha, 410013, Hunan, China
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18
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Yao J, Ma C, Feng K, Tan G, Wen Q. Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective. Biomolecules 2022; 12:1565. [PMID: 36358919 PMCID: PMC9687214 DOI: 10.3390/biom12111565] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 10/15/2023] Open
Abstract
Autophagy is a critical cellular adaptive response in tumor formation. Nutritional deficiency and hypoxia exacerbate autophagic flux in established malignancies, promoting tumor cell proliferation, migration, metastasis, and resistance to therapeutic interventions. Pro-survival autophagy inhibition may be a promising treatment option for advanced cancer. Furthermore, excessive or persistent autophagy is cytotoxic, resulting in tumor cell death. Targeted autophagy activation has also shown significant promise in the fight against tumor drug resistance. Several research groups have examined the ability of natural products (NPs) such as alkaloids, terpenoids, polyphenols, and anthraquinones to serve as autophagy inhibitors or activators. The data support the capacity of NPs that promote lethal autophagy or inhibit pro-survival autophagy from being employed against tumor drug resistance. This paper discusses the potential applications of NPs that regulate autophagy in the fight against tumor drug resistance, some limitations of the current studies, and future research needs and priorities.
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Affiliation(s)
- Jiaqi Yao
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Chi Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Kaixuan Feng
- Department of Anesthesiology, The Affiliated Xinhua Hospital of Dalian University, Dalian 116021, China
| | - Guang Tan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Qingping Wen
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
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19
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Tumor cell dormancy: Molecular mechanisms, and pharmacological approaches to target dormant cells for countering tumor. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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20
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Shan E, Hao Y, Wang H, Zhang Z, Hu J, Wang G, Liu W, Yan B, Hiroaki H, Yang J. Differentiated embryonic chondrocyte expressed gene-1 (DEC1) enhances the development of colorectal cancer with an involvement of the STAT3 signaling. Neoplasia 2022; 27:100783. [PMID: 35334277 PMCID: PMC8956864 DOI: 10.1016/j.neo.2022.100783] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 03/03/2022] [Accepted: 03/03/2022] [Indexed: 01/25/2023]
Abstract
Colorectal cancer (CRC) is the second deadly and the third most common malignancy worldwide. It has been projected that annual new cases of CRC will increase by 63% in 2040, constituting an even greater health challenge for decades to come. This study has linked DEC1 (differentiated embryonic chondrocyte expressed gene 1) to the pathogenesis of CRC. Based on the analysis of patient samples and database data, DEC1 is expressed much higher in CRC than the adjacent normal tissues. CRC patients with higher DEC1 expression have a shorter survival time. The carcinogenesis protocol with azoxymethane/dextran sulfate induces a higher number of tumors with larger sizes in DEC1+/+ than DEC1−/− mice. Overexpression of DEC1 increases the expression of proliferation- and antiapoptosis-related genes, but decreases the level of proapoptotic genes. Mechanistically, this study has shown that DEC1 is functionally looped to the IL-6/STAT3 signaling pathway (interleukin-6/signal transducer and activator of transcription 3). IL-6 induces DEC1, and DEC1 enhances the phosphorylation of STAT3, resulting in increased pSTAT3/STAT3 ratio. DEC1 and STAT3 are present in reciprocal immunocomplexes, pointing to physical interactions (presumably with pSTAT3). These findings establish that DEC1 is a CRC enhancer. The enhancement is achieved largely through the IL-6/STAT3 pathway. The potential of the physical interaction between DEC1 and STAT3 will likely serve as a foundation to develop intervention strategies for CRC prevention and therapy.
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21
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Resveratrol Contrasts IL-6 Pro-Growth Effects and Promotes Autophagy-Mediated Cancer Cell Dormancy in 3D Ovarian Cancer: Role of miR-1305 and of Its Target ARH-I. Cancers (Basel) 2022; 14:cancers14092142. [PMID: 35565270 PMCID: PMC9101105 DOI: 10.3390/cancers14092142] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 01/18/2023] Open
Abstract
Tumor dormancy is the extended period during which patients are asymptomatic before recurrence, and it represents a difficult phenomenon to target pharmacologically. The relapse of tumors, for instance arising from the interruption of dormant metastases, is frequently observed in ovarian cancer patients and determines poor survival. Inflammatory cytokines present in the tumor microenvironment likely contribute to such events. Cancer cell dormancy and autophagy are interconnected at the molecular level through ARH-I (DIRAS3) and BECLIN-1, two tumor suppressors often dysregulated in ovarian cancers. IL-6 disrupts autophagy in ovarian cancer cells via miRNAs downregulation of ARH-I, an effect contrasted by the nutraceutical protein restriction mimetic resveratrol (RV). By using three ovarian cancer cell lines with different genetic background in 2D and 3D models, the latter mimicking the growth of peritoneal metastases, we show that RV keeps the cancer cells in a dormant-like quiescent state contrasting the IL-6 growth-promoting activity. Mechanistically, this effect is mediated by BECLIN-1-dependent autophagy and relies on the availability of ARH-I. We also show that ARH-I (DIRAS3) is a bona fide target of miR-1305, a novel oncomiRNA upregulated by IL-6 and downregulated by RV. Clinically relevant, bioinformatic analysis of a transcriptomic database showed that the high expression of DIRAS3 and MAP1LC3B mRNAs together with that of CDKN1A, directing a cellular dormant phenotype, predicts better overall survival in ovarian cancer patients, and this correlates with MIR1305 downregulation. The possibility of maintaining a permanent cell dormancy in ovarian cancer by the chronic administration of RV should be considered as a therapeutic option to prevent the "awakening" of cancer cells in response to a permissive microenvironment, thus limiting the risk of tumor relapse and metastasis.
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22
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Rahat MA. Mini-Review: Can the Metastatic Cascade Be Inhibited by Targeting CD147/EMMPRIN to Prevent Tumor Recurrence? Front Immunol 2022; 13:855978. [PMID: 35418981 PMCID: PMC8995701 DOI: 10.3389/fimmu.2022.855978] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/07/2022] [Indexed: 12/05/2022] Open
Abstract
Solid tumors metastasize very early in their development, and once the metastatic cell is lodged in a remote organ, it can proliferate to generate a metastatic lesion or remain dormant for long periods. Dormant cells represent a real risk for future tumor recurrence, but because they are typically undetectable and insensitive to current modalities of treatment, it is difficult to treat them in time. We describe the metastatic cascade, which is the process that allows tumor cells to detach from the primary tumor, migrate in the tissue, intravasate and extravasate the lymphatics or a blood vessel, adhere to a remote tissue and eventually outgrow. We focus on the critical enabling role of the interactions between tumor cells and immune cells, especially macrophages, in driving the metastatic cascade, and on those stages that can potentially be targeted. In order to prevent the metastatic cascade and tumor recurrence, we would need to target a molecule that is involved in all of the steps of the process, and evidence is brought to suggest that CD147/EMMPRIN is such a protein and that targeting it blocks metastasis and prevents tumor recurrence.
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Affiliation(s)
- Michal A Rahat
- Immunotherapy Laboratory, Carmel Medical Center, Haifa, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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Chen Y, Gibson SB. Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells. Front Cell Dev Biol 2022; 10:823251. [PMID: 35309946 PMCID: PMC8926073 DOI: 10.3389/fcell.2022.823251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 02/14/2022] [Indexed: 12/19/2022] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive type of brain cancer in adults, with temozolomide (TMZ) being widely used as the standard chemotherapy drug for its treatment. However, GBM frequently becomes resistant to TMZ treatment due to various mechanisms including amplification and mutations of the epidermal growth factor receptor (EGFR), where EGFR variant III (EGFRvIII) is the most common EGFR mutation. Autophagy (macroautophagy) is an intracellular “self-degradation” process involving the lysosome. It mainly plays a pro-cell survival role contributing to drug resistance in cancers including GBM, but, under some conditions, it can induce cell death called autophagy-induced cell death (AuICD). We recently published that TSSC4 (tumor suppressing subtransferable candidate 4) is a novel tumor suppressor and a novel autophagy inhibitor that inhibits cancer cell growth through its interacting with the autophagy protein LC3. In this brief research report, we demonstrate that cell death induced by TMZ in GBM cells is inhibited by overexpression of TSSC4. TSSC4 overexpression also prevents TMZ-induced autophagy but not when TSSC4 is mutated in its conserved LC3-interacting region. When EGFRvIII was expressed in GBM cells, TSSC4 protein was increased and TMZ-induced cell death was decreased. Knockout of TSSC4 in EGFRvIII-expressing GBM cells increased TMZ-induced autophagy and cell death. This cell death was decreased by autophagy inhibition, suggesting that TSSC4 downregulation promotes TMZ-induced AuICD. This indicates that TSSC4 is a novel target to sensitize GBM cells to TMZ treatment.
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Affiliation(s)
- Yongqiang Chen
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Spencer B Gibson
- Department of Biochemistry and Medical Genetics, Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
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