|
1
|
Azad MG, Russell T, Gu X, Zhao X, Richardson V, Wijesinghe TP, Babu G, Guo X, Kaya B, Dharmasivam M, Deng Z, Richardson DR. NDRG1 and its Family Members: More than Just Metastasis Suppressor Proteins and Targets of Thiosemicarbazones. J Biol Chem 2025:110230. [PMID: 40378957 DOI: 10.1016/j.jbc.2025.110230] [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: 03/15/2025] [Revised: 04/19/2025] [Accepted: 05/05/2025] [Indexed: 05/19/2025] Open
Abstract
N-Myc downstream regulated gene-1 (NDRG1) and the other three members of this family (NDRG2, 3, and 4) play various functional roles in the cellular stress response, differentiation, migration, and development. These proteins are involved in regulating key signaling proteins and pathways that are often dysregulated in cancer, such as EGFR, PI3K/AKT, c-Met, and the Wnt pathway. NDRG1 is the primary, well-examined member of the NDRG family, and is generally characterized as a metastasis suppressor that inhibits the first step in metastasis, the epithelial-mesenchymal transition. While NDRG1 is well-studied, emerging evidence suggests NDRG2, NDRG3, and NDRG4 also play significant roles in modulating oncogenic signaling and cellular homeostasis. NDRG family members are regulated by multiple mechanisms, including transcriptional control by hypoxia-inducible factors, p53, and Myc, as well as post-translational modifications such as phosphorylation, ubiquitination, and acetylation. Pharmacological targeting of the NDRG family is a therapeutic strategy against cancer. For instance, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) have been extensively shown to up-regulate NDRG1 expression, leading to metastasis suppression and inhibition of tumor growth in multiple cancer models. Similarly, targeting NDRG2 demonstrates its pro-apoptotic and anti-proliferative effects, particularly in glioblastoma and colorectal cancer. This review provides a comprehensive analysis of the structural features, regulatory mechanisms, and biological functions of the NDRG family and their roles in cancer and neurodegenerative diseases. Additionally, NDRG1-4 are explored as therapeutic targets in oncology, focusing on recent advances in anti-cancer agents that induce the expression of these proteins. Implications for future research and clinical applications are also discussed.
Collapse
Affiliation(s)
- Mahan Gholam Azad
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Tiffany Russell
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xuanling Gu
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xiao Zhao
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Vera Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Tharushi P Wijesinghe
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Golap Babu
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xinnong Guo
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Busra Kaya
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Mahendiran Dharmasivam
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Zhao Deng
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Des R Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
| |
Collapse
|
|
2
|
Meng K, Jia H, Hou X, Zhu Z, Lu Y, Feng Y, Feng J, Xia Y, Tan R, Cui F, Yuan J. Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies. Biomedicines 2025; 13:327. [PMID: 40002740 PMCID: PMC11852430 DOI: 10.3390/biomedicines13020327] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.
Collapse
Affiliation(s)
- Kai Meng
- Lin He’s Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining 272067, China;
| | - Haocheng Jia
- College of Clinical Medicine, Jining Medical University, Jining 272067, China; (H.J.); (X.H.); (Z.Z.); (Y.L.); (Y.F.)
| | - Xiaoqing Hou
- College of Clinical Medicine, Jining Medical University, Jining 272067, China; (H.J.); (X.H.); (Z.Z.); (Y.L.); (Y.F.)
| | - Ziming Zhu
- College of Clinical Medicine, Jining Medical University, Jining 272067, China; (H.J.); (X.H.); (Z.Z.); (Y.L.); (Y.F.)
| | - Yuguang Lu
- College of Clinical Medicine, Jining Medical University, Jining 272067, China; (H.J.); (X.H.); (Z.Z.); (Y.L.); (Y.F.)
| | - Yingying Feng
- College of Clinical Medicine, Jining Medical University, Jining 272067, China; (H.J.); (X.H.); (Z.Z.); (Y.L.); (Y.F.)
| | - Jingwen Feng
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China;
| | - Yong Xia
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China;
| | - Rubin Tan
- College of Basic Medical, Xuzhou Medical University, Xuzhou 221004, China;
| | - Fen Cui
- Educational Institute of Behavioral Medicine, Jining Medical University, Jining 272067, China
| | - Jinxiang Yuan
- Lin He’s Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining 272067, China;
| |
Collapse
|
|
3
|
Lu S, Chen S, Zhang Y, Mou X, Li M, Zhu S, Chen X, Strandin TM, Jiang Y, Xiang Z, Liu Y, Xiong H, Guo D, Chen L, Li Y, Hou W, Luo F. Hantaan virus glycoprotein Gc induces NEDD4-dependent PTEN ubiquitination and degradation to escape the restriction of autophagosomes and facilitate viral propagation. FASEB J 2025; 39:e70295. [PMID: 39792131 PMCID: PMC11721564 DOI: 10.1096/fj.202401916r] [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: 08/17/2024] [Revised: 11/30/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025]
Abstract
Hantaan virus (HTNV) infection causes severe hemorrhagic fever with renal syndrome (HFRS) in humans and the infectious process can be regulated by autophagy. The phosphatase and tensin homolog (PTEN) protein has antiviral effects and plays a critical role in the autophagy pathway. However, the relationship between PTEN and HTNV infection is not clear and whether PTEN-regulated autophagy involves in HTNV replication is unknown. Here, we identified that HTNV infection inhibits PTEN expression in vitro and in vivo. The HTNV glycoprotein Gc promotes PTEN ubiquitination and degradation through 26S-proteasome pathway via the E3 ubiquitin ligase NEDD4. In addition, knockdown of PTEN prevents autophagy and increases HTNV production, while overexpression of PTEN induces autophagosome formation which can wrap HTNV particles, thus leading to restrain the production of progeny viruses. Altogether, our findings reveal the role of PTEN in HTNV infection by autophagy, highlighting the potential importance of PTEN and autophagy in the treatment of HFRS diseases.
Collapse
Affiliation(s)
- Shuang Lu
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
- College of Life SciencesSouth‐Central Minzu UniversityWuhanHubeiChina
| | - Shuliang Chen
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Yuqing Zhang
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Xiaoli Mou
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Mingyang Li
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Shaowei Zhu
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Xingyuan Chen
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Tomas M. Strandin
- Department of Virology, MedicumUniversity of HelsinkiHelsinkiFinland
| | - Yale Jiang
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
- Shenzhen Research InstituteWuhan UniversityShenzhenGuangdongChina
| | - Zhoufu Xiang
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
- Shenzhen Research InstituteWuhan UniversityShenzhenGuangdongChina
| | - Yuanyuan Liu
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Hairong Xiong
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
| | - Deyin Guo
- Guangzhou LaboratoryGuangzhou International Bio‐IslandGuangzhouGuangdongChina
| | - Liangjun Chen
- Department of Laboratory MedicineZhongnan Hospital of Wuhan UniversityWuhanHubeiChina
| | - Yirong Li
- Department of Laboratory MedicineZhongnan Hospital of Wuhan UniversityWuhanHubeiChina
| | - Wei Hou
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
- Shenzhen Research InstituteWuhan UniversityShenzhenGuangdongChina
- School of Public HealthWuhan UniversityWuhanHubeiChina
- Hubei Provincial Key Laboratory of Allergy and ImmunologyWuhanHubeiChina
| | - Fan Luo
- State Key Laboratory of Virology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanHubeiChina
- Hubei Provincial Key Laboratory of Allergy and ImmunologyWuhanHubeiChina
- Pingyuan LaboratoryXinxiangHenanChina
| |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
Guo N, Xia Y, He N, Cheng H, Zhang L, Liu J. IRGM Deficiency Exacerbates Sepsis-Induced Acute Lung Injury by Inhibiting Autophagy Through the AKT/mTOR Signaling Pathway. J Inflamm Res 2024; 17:10255-10272. [PMID: 39654860 PMCID: PMC11626208 DOI: 10.2147/jir.s496687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/23/2024] [Indexed: 12/12/2024] Open
Abstract
Background Sepsis is a life-threatening condition characterized by organ dysfunction due to an impaired immune response to infection. The lungs are highly susceptible to infection, often resulting in acute lung injury (ALI). The immune-related GTPase M (IRGM) and its murine homolog Irgm1 mediate autophagy and are implicated in inflammatory diseases, yet their roles in sepsis-induced ALI remain unclear. Methods We used RNA sequencing and bioinformatics to explore IRGM regulation. Sepsis-induced ALI was modeled in mice using cecal ligation and puncture (CLP). An in vitro model was created by stimulating A549 cells with lipopolysaccharide (LPS). Results In A549 cells, LPS treatment induced upregulation of IRGM expression and enhanced autophagy levels. IRGM knockdown exacerbated LPS-induced ALI, characterized by suppressed autophagy and increased apoptosis, along with significantly elevated levels of p-AKT and p-mTOR. Further investigation revealed that treatment with the AKT inhibitor MK2206 effectively reversed the autophagy inhibition caused by IRGM knockdown and reduced apoptosis. These findings suggest that the AKT/mTOR signaling pathway plays a crucial role in IRGM-mediated protection against sepsis-related ALI. Conclusion This study identifies the protective role of IRGM in sepsis-induced ALI and reveals that IRGM mitigates ALI by promoting autophagy through inhibition of the AKT/mTOR pathway. These findings provide insights into the pathogenesis of sepsis-related ALI and highlight IRGM as a potential therapeutic target.
Collapse
Affiliation(s)
- Na Guo
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Yu Xia
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Nannan He
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Huixin Cheng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Lei Zhang
- Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Center Hospital), Lanzhou, Gansu Province, People’s Republic of China
| | - Jian Liu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
- Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Center Hospital), Lanzhou, Gansu Province, People’s Republic of China
| |
Collapse
|
|
6
|
Meena D, Jha S. Autophagy in glioblastoma: A mechanistic perspective. Int J Cancer 2024; 155:605-617. [PMID: 38716809 DOI: 10.1002/ijc.34991] [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: 01/29/2024] [Revised: 03/28/2024] [Accepted: 04/12/2024] [Indexed: 06/20/2024]
Abstract
Glioblastoma (GBM) is one of the most lethal malignancies in humans. Even after surgical resection and aggressive radio- or chemotherapies, patients with GBM can survive for less than 14 months. Extreme inter-tumor and intra-tumor heterogeneity of GBM poses a challenge for resolving recalcitrant GBM pathophysiology. GBM tumor microenvironment (TME) exhibits diverse heterogeneity in cellular composition and processes contributing to tumor progression and therapeutic resistance. Autophagy is such a cellular process; that demonstrates a cell-specific and TME context-dependent role in GBM progression, leading to either the promotion or suppression of GBM progression. Autophagy can regulate GBM cell function directly via regulation of survival, migration, and invasion, or indirectly by affecting GBM TME composition such as immune cell population, tumor metabolism, and glioma stem cells. This review comprehensively investigates the role of autophagy in GBM pathophysiology.
Collapse
Affiliation(s)
- Durgesh Meena
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Sushmita Jha
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| |
Collapse
|
|
7
|
Du L, Zhang Q, Li Y, Li T, Deng Q, Jia Y, Lei K, Kan D, Xie F, Huang S. Research progress on the role of PTEN deletion or mutation in the immune microenvironment of glioblastoma. Front Oncol 2024; 14:1409519. [PMID: 39206155 PMCID: PMC11349564 DOI: 10.3389/fonc.2024.1409519] [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: 03/30/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the anti-tumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma.
Collapse
Affiliation(s)
- Leiya Du
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Qian Zhang
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Yi Li
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Ting Li
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Qingshan Deng
- Department of Neurosurgery, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Yuming Jia
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Kaijian Lei
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Daohong Kan
- Department of Burn and Plastic Surgery, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Fang Xie
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Shenglan Huang
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| |
Collapse
|
|
8
|
Xie W, Wang Z, Wang J, Wang X, Guan H. Investigating the molecular mechanisms of microRNA‑409‑3p in tumor progression: Towards targeted therapeutics (Review). Int J Oncol 2024; 65:67. [PMID: 38757364 PMCID: PMC11155714 DOI: 10.3892/ijo.2024.5655] [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] [Accepted: 05/02/2024] [Indexed: 05/18/2024] Open
Abstract
MicroRNAs (miRNAs) are a group of non‑coding RNAs that exert master regulatory functions in post‑-transcriptional gene expression. Accumulating evidence shows that miRNAs can either promote or suppress tumorigenesis by regulating different target genes or pathways and may be involved in the occurrence of carcinoma. miR‑409‑3p is dysregulated in a variety of malignant cancers. It plays a fundamental role in numerous cellular biological processes, such as cell proliferation, apoptosis, migration, invasion, autophagy, angiogenesis and glycolysis. In addition, studies have shown that miR‑409‑3p is expected to become a non‑invasive biomarker. Identifying the molecular mechanisms underlying miR‑409‑3p‑mediated tumor progression will help investigate miR‑409‑3p‑based targeted therapy for human cancers. The present review comprehensively summarized the recently published literature on miR‑409‑3p, with a focus on the regulation and function of miR‑409‑3p in various types of cancer, and discussed the clinical implications of miR‑409‑3p, providing new insight for the diagnosis and treatment of cancers.
Collapse
Affiliation(s)
- Wenjie Xie
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Zhichao Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Junke Wang
- Department of Cardiology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xiu Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Hongzai Guan
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| |
Collapse
|
|
9
|
Chen J, Ding W, Zhang Z, Li Q, Wang M, Feng J, Zhang W, Cao L, Ji X, Nie S, Sun Z. Shenfu injection targets the PI3K-AKT pathway to regulate autophagy and apoptosis in acute respiratory distress syndrome caused by sepsis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155627. [PMID: 38696924 DOI: 10.1016/j.phymed.2024.155627] [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: 10/28/2023] [Revised: 03/30/2024] [Accepted: 04/09/2024] [Indexed: 05/04/2024]
Abstract
BACKGROUND Sepsis is a life-threatening organ dysfunction caused by an exaggerated response to infection. In the lungs, one of the most susceptible organs, this can manifest as acute respiratory distress syndrome (ARDS). Shenfu (SF) injection is a prominent traditional Chinese medicine used to treat sepsis. However, the exact mechanism of its action has rarely been reported in the literature. PURPOSE In the present study, we detected the protective effect of SF injection on sepsis-induced ARDS and explored its underlying mechanism. METHODS We investigated the potential targets and regulatory mechanisms of SF injections using a combination of network pharmacology and RNA sequencing. This study was conducted both in vivo and in vitro using a mouse model of ARDS and lipopolysaccharide (LPS)-stimulated MLE-12 cells, respectively. RESULTS The results showed that SF injection could effectively inhibit inflammation, oxidative stress, and apoptosis to alleviate LPS-induced ARDS. SF inhibited the PI3K-AKT pathway, which controls autophagy and apoptosis. Subsequently, MLE-12 cells were treated with 3-methyladenine to assess its effects on autophagy and apoptosis. Additional experiments were conducted by adding rapamycin, an mTOR antagonist, or SC79, an AKT agonist, to investigate the effects of SF injection on autophagy, apoptosis, and the PI3K-AKT pathway. CONCLUSION Overall, we found that SF administration could enhance autophagic activity, reduce apoptosis, suppress inflammatory responses and oxidative stress, and inhibit the PI3K-AKT pathway, thus ameliorating sepsis-induced ARDS.
Collapse
Affiliation(s)
- Juan Chen
- Department of Emergency Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210002, PR China; Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China; Department of Emergency Medicine, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu Province 221000, PR China
| | - Weichao Ding
- Department of Emergency Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210002, PR China; Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China; Department of Emergency Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
| | - Zhe Zhang
- Department of Emergency Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210002, PR China; Department of Medical Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
| | - Quan Li
- Department of Emergency Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210002, PR China
| | - Mengmeng Wang
- Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China
| | - Jing Feng
- Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China
| | - Wei Zhang
- Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China
| | - Liping Cao
- Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China
| | - Xiaohang Ji
- Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China
| | - Shinan Nie
- Department of Emergency Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210002, PR China; Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China.
| | - Zhaorui Sun
- Department of Emergency Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210002, PR China; Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, PR China.
| |
Collapse
|
|
10
|
Ayub A, Hasan MK, Mahmud Z, Hossain MS, Kabir Y. Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications. Med Oncol 2024; 41:183. [PMID: 38902544 DOI: 10.1007/s12032-024-02417-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/28/2024] [Indexed: 06/22/2024]
Abstract
Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagy can potentially advocate for the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer.
Collapse
Affiliation(s)
- Afia Ayub
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Md Kamrul Hasan
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh.
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St. W., Hamilton, L8S 4K1, Canada.
- Department of Public Health, North South University, Dhaka, Bangladesh.
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| | - Md Sabbir Hossain
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| |
Collapse
|
|
11
|
Lin Z, Long F, Kang R, Klionsky DJ, Yang M, Tang D. The lipid basis of cell death and autophagy. Autophagy 2024; 20:469-488. [PMID: 37768124 PMCID: PMC10936693 DOI: 10.1080/15548627.2023.2259732] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/25/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
ABBREVIATIONS ACSL: acyl-CoA synthetase long chain family; DISC: death-inducing signaling complex; DAMPs: danger/damage-associated molecular patterns; Dtgn: dispersed trans-Golgi network; FAR1: fatty acyl-CoA reductase 1; GPX4: glutathione peroxidase 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; LPS: lipopolysaccharide; MUFAs: monounsaturated fatty acids; MOMP: mitochondrial outer membrane permeabilization; MLKL, mixed lineage kinase domain like pseudokinase; oxPAPC: oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; OxPCs: oxidized phosphatidylcholines; PUFAs: polyunsaturated fatty acids; POR: cytochrome p450 oxidoreductase; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; RIPK1: receptor interacting serine/threonine kinase 1; SPHK1: sphingosine kinase 1; SOAT1: sterol O-acyltransferase 1; SCP2: sterol carrier protein 2; SFAs: saturated fatty acids; SLC47A1: solute carrier family 47 member 1; SCD: stearoyl-CoA desaturase; VLCFA: very long chain fatty acids.
Collapse
Affiliation(s)
- Zhi Lin
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Pediatric Cancer, Changsha, Hunan, China
| | - Fei Long
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Postdoctoral Research Station of Basic Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Minghua Yang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Pediatric Cancer, Changsha, Hunan, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| |
Collapse
|
|
12
|
Kim R, Kin T, Beck WT. Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy. Cancers (Basel) 2024; 16:984. [PMID: 38473345 DOI: 10.3390/cancers16050984] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1-mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy.
Collapse
Affiliation(s)
- Ryungsa Kim
- Department of Breast Surgery, Hiroshima Mark Clinic, 1-4-3F, 2-Chome Ohte-machi, Naka-ku, Hiroshima 730-0051, Japan
| | - Takanori Kin
- Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - William T Beck
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA
| |
Collapse
|
|
13
|
Das N, Mukherjee S, Das A, Gupta P, Bandyopadhyay A, Chattopadhyay S. Intra-tumor ROS amplification by melatonin interferes in the apoptosis-autophagy-inflammation-EMT collusion in the breast tumor microenvironment. Heliyon 2024; 10:e23870. [PMID: 38226217 PMCID: PMC10788523 DOI: 10.1016/j.heliyon.2023.e23870] [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: 03/12/2023] [Revised: 11/21/2023] [Accepted: 12/14/2023] [Indexed: 01/17/2024] Open
Abstract
Epidemiological as well as experimental studies have established that the pineal hormone melatonin has inhibitory effects on different types of cancers. Several mechanisms have been proposed for the anticancer activities of melatonin, but the fundamental molecular pathways still require clarity. We developed a mouse model of breast cancer using Ehrlich's ascites carcinoma (injected in the 4th mammary fat pad of female Swiss albino mice) and investigated the possibility of targeting the autophagy-inflammation-EMT colloquy to restrict breast tumor progression using melatonin as intervention. Contrary to its conventional antioxidant role, melatonin was shown to augment intracellular ROS and initiate ROS-dependent apoptosis in our system, by modulating the p53/JNK & NF-κB/pJNK expressions/interactions. Melatonin-induced ROS promoted SIRT1 activity. Interplay between SIRT1 and NF-κB/p65 is known to play a pivotal role in regulating the crosstalk between autophagy and inflammation. Persistent inflammation in the tumor microenvironment and subsequent activation of the IL-6/STAT3/NF-κB feedback loop promoted EMT and suppression of autophagy through activation of PI3K/Akt/mTOR signaling pathway. Melatonin disrupted NF-κB/SIRT1 interactions blocking IL-6/STAT3/NF-κB pathway. This led to reversal of pro-inflammatory bias in the breast tumor microenvironment and augmented autophagic responses. The interactions between p62/Twist1, NF-κB/Beclin1 and NF-κB/Slug were altered by melatonin to strike a balance between autophagy, inflammation and EMT, leading to tumor regression. This study provides critical insights into how melatonin could be utilized in treating breast cancer via inhibition of the PI3K/Akt/mTOR signaling and differential modulation of SIRT1 and NF-κB proteins, leading to the establishment of apoptotic and autophagic fates in breast cancer cells.
Collapse
Affiliation(s)
- Nirmal Das
- Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, West Bengal 700009, India
| | - Sudeshna Mukherjee
- Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, West Bengal 700009, India
- Department of Physiology and Allied Sciences, Amity Institute of Health Allied Sciences, Amity University, Uttar Pradesh, India
| | - Ankur Das
- Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, West Bengal 700009, India
| | - Payal Gupta
- Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, West Bengal 700009, India
| | - Amit Bandyopadhyay
- Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, West Bengal 700009, India
| | - Sreya Chattopadhyay
- Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, West Bengal 700009, India
- Centre for Research in Nanoscience and Nanotechnology (CRNN), University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata-700098, India
| |
Collapse
|
|
14
|
De D, Ghosh G, Karmakar P. Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation. Exp Cell Res 2024; 434:113872. [PMID: 38072303 DOI: 10.1016/j.yexcr.2023.113872] [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: 08/04/2023] [Revised: 11/30/2023] [Accepted: 12/03/2023] [Indexed: 12/17/2023]
Abstract
Autophagy is involved in the entirety of cellular survival, homeostasis and death which becomes more self-evident when its dysregulation is implicated in several pathological conditions. PTEN positively regulates autophagy and like other proteins undergo post-translational modifications. It is crucial to investigate the relationship between PTEN and autophagy as it is generally observed to be negligible in PTEN deficient cancer cells. Here, we have shown that such modifications of PTEN namely sumoylation and phosphorylation upregulates and downregulates autophagy respectively. Transfection of plasmid containing full length PTEN in PTEN-negative prostate cancer cell line PC3, induced autophagy on further starvation. When a sumoylation-deficient mutant of PTEN was transfected and cells were put under similar starvation, a decline in autophagy was observed. On the other hand, cells transfected with phosphorylation-deficient mutant of PTEN showed elevated expression of autophagy. Contrarily, transfection with phosphorylation-mimicking mutant caused reduced expression of autophagy. On further analysis, it was detected that PTEN's association with the plasma membrane was under positive and negative influence from its sumoylation and phosphorylation respectively. This association is integral as it is the foremost site for PTEN to oppose PI3K/AKT pathway and consequently upregulate autophagy. Thus, this study indicates that sumoylation and phosphorylation of PTEN can control autophagy via its cell membrane association.
Collapse
Affiliation(s)
- Debojyoti De
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
| | - Ginia Ghosh
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
| | - Parimal Karmakar
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
| |
Collapse
|
|
15
|
Zhang Y, Yang L, Ou Y, Hu R, Du G, Luo S, Wu F, Wang H, Xie Z, Zhang Y, He C, Ma C, Gong T, Zhang L, Zhang Z, Sun X. Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity. Acta Pharm Sin B 2024; 14:350-364. [PMID: 38261817 PMCID: PMC10792967 DOI: 10.1016/j.apsb.2023.06.006] [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: 04/19/2023] [Revised: 05/16/2023] [Accepted: 06/02/2023] [Indexed: 01/25/2024] Open
Abstract
Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.
Collapse
Affiliation(s)
- Yongshun Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Lan Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yangsen Ou
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Rui Hu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Guangsheng Du
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Shuang Luo
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Fuhua Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Hairui Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zhiqiang Xie
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yu Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chunting He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Cheng Ma
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ling Zhang
- Med-X Center for Materials, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Zhirong Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xun Sun
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
16
|
Dupont N, Claude-Taupin A, Codogno P. A historical perspective of macroautophagy regulation by biochemical and biomechanical stimuli. FEBS Lett 2024; 598:17-31. [PMID: 37777819 DOI: 10.1002/1873-3468.14744] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/02/2023]
Abstract
Macroautophagy is a lysosomal degradative pathway for intracellular macromolecules, protein aggregates, and organelles. The formation of the autophagosome, a double membrane-bound structure that sequesters cargoes before their delivery to the lysosome, is regulated by several stimuli in multicellular organisms. Pioneering studies in rat liver showed the importance of amino acids, insulin, and glucagon in controlling macroautophagy. Thereafter, many studies have deciphered the signaling pathways downstream of these biochemical stimuli to control autophagosome formation. Two signaling hubs have emerged: the kinase mTOR, in a complex at the surface of lysosomes which is sensitive to nutrients and hormones; and AMPK, which is sensitive to the cellular energetic status. Besides nutritional, hormonal, and energetic fluctuations, many organs have to respond to mechanical forces (compression, stretching, and shear stress). Recent studies have shown the importance of mechanotransduction in controlling macroautophagy. This regulation engages cell surface sensors, such as the primary cilium, in order to translate mechanical stimuli into biological responses.
Collapse
Affiliation(s)
- Nicolas Dupont
- INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker-Enfants Malades, Université Paris Cité, France
| | - Aurore Claude-Taupin
- INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker-Enfants Malades, Université Paris Cité, France
| | - Patrice Codogno
- INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker-Enfants Malades, Université Paris Cité, France
| |
Collapse
|
|
17
|
Xu JY, Fan JX, Hu M, Zeng J. Microorganism-regulated autophagy in gastrointestinal cancer. PeerJ 2023; 11:e16130. [PMID: 37786582 PMCID: PMC10541808 DOI: 10.7717/peerj.16130] [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: 04/13/2023] [Accepted: 08/28/2023] [Indexed: 10/04/2023] Open
Abstract
Gastrointestinal cancer has always been one of the most urgent problems to be solved, and it has become a major global health issue. Microorganisms in the gastrointestinal tract regulate normal physiological and pathological processes. Accumulating evidence reveals the role of the imbalance in the microbial community during tumorigenesis. Autophagy is an important intracellular homeostatic process, where defective proteins and organelles are degraded and recycled under stress. Autophagy plays a dual role in tumors as both tumor suppressor and tumor promoter. Many studies have shown that autophagy plays an important role in response to microbial infection. Here, we provide an overview on the regulation of the autophagy signaling pathway by microorganisms in gastrointestinal cancer.
Collapse
Affiliation(s)
- Jun-Yu Xu
- Chongqing Normal University, Chongqing, China
| | | | - Min Hu
- Chongqing Normal University, Chongqing, China
| | - Jun Zeng
- Chongqing Normal University, Chongqing, China
| |
Collapse
|
|
18
|
Shao J, Jin Y, Jin C. A new approach to overcoming resistance to immunotherapy: nanotechnology. Front Oncol 2023; 13:1210245. [PMID: 37637050 PMCID: PMC10457008 DOI: 10.3389/fonc.2023.1210245] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/27/2023] [Indexed: 08/29/2023] Open
Abstract
Immunotherapy for immune response has ushered in a new era of cancer treatment. In recent years, new immunotherapeutic agents have been introduced into clinical trials and even approved for marketing. However, the widespread use of immunotherapeutic agents faces an unavoidable challenge: immunotherapy does not work at all for some patients, or has good efficacy in the initial phase, but immunotherapy resistance develops within a short period of time, and immunotherapy can also cause serious adverse effects such as autoimmune inflammation and non-specific inflammation. How to enable patients to overcome drug resistance, reduce the toxic side effects of drugs, enhance patient compliance and improve patient survival has become a problem that clinicians have to face. The advent of nanotechnology provides an encouraging platform for immunotherapy. It can not only improve the bioavailability and stability of drugs and reduce toxic side effects, but also reduce resistance to immunotherapy. Here, we discuss these research advances and discuss potential challenges and future directions.
Collapse
Affiliation(s)
- Jiangbo Shao
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Ying Jin
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chunxiang Jin
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| |
Collapse
|
|
19
|
Shen S, Shao Y, Li C. Different types of cell death and their shift in shaping disease. Cell Death Discov 2023; 9:284. [PMID: 37542066 PMCID: PMC10403589 DOI: 10.1038/s41420-023-01581-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 07/16/2023] [Accepted: 07/26/2023] [Indexed: 08/06/2023] Open
Abstract
Cell death is the irreversible stop of life. It is also the basic physiological process of all organisms which involved in the embryonic development, organ maintenance and autoimmunity of the body. In recent years, we have gained more comprehension of the mechanism in cell death and have basically clarified the different types of "programmed cell death", such as apoptosis, necroptosis, autophagy, and pyroptosis, and identified some key genes in these processes. However, in these previous studies, the conversion between different cell death modes and their application in diseases are rarely explored. To sum up, although many valued discoveries have been discovered in the field of cell death in recent years, there are still many unknown problems to be solved in this field. Facts have proved that cell death is a very complex game, and a series of core players have the ability to destroy the delicate balance of the cell environment, from survival to death, from anti-inflammatory to pro-inflammatory. With the thorough research of the complex regulatory mechanism of cell death, there will certainly be exciting new research in this field in the next few years. The sake of this paper is to emphasize the complex mechanism of overturning the balance between different cell fates and provide relevant theoretical basis for the connection between cell death transformation and disease treatment in the future.
Collapse
Affiliation(s)
- Sikou Shen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China
| | - Yina Shao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China
| | - Chenghua Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China.
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, PR China.
| |
Collapse
|
|
20
|
Liu Y, Wang L, Yang G, Chi X, Liang X, Zhang Y. Sirtuins: Promising Therapeutic Targets to Treat Ischemic Stroke. Biomolecules 2023; 13:1210. [PMID: 37627275 PMCID: PMC10452362 DOI: 10.3390/biom13081210] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 07/28/2023] [Accepted: 07/30/2023] [Indexed: 08/27/2023] Open
Abstract
Stroke is a major cause of mortality and disability globally, with ischemic stroke (IS) accounting for over 80% of all stroke cases. The pathological process of IS involves numerous signal molecules, among which are the highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes known as sirtuins (SIRTs). SIRTs modulate various biological processes, including cell differentiation, energy metabolism, DNA repair, inflammation, and oxidative stress. Importantly, several studies have reported a correlation between SIRTs and IS. This review introduces the general aspects of SIRTs, including their distribution, subcellular location, enzyme activity, and substrate. We also discuss their regulatory roles and potential mechanisms in IS. Finally, we describe the current therapeutic methods based on SIRTs, such as pharmacotherapy, non-pharmacological therapeutic/rehabilitative interventions, epigenetic regulators, potential molecules, and stem cell-derived exosome therapy. The data collected in this study will potentially contribute to both clinical and fundamental research on SIRTs, geared towards developing effective therapeutic candidates for future treatment of IS.
Collapse
Affiliation(s)
- Yue Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Y.L.); (L.W.); (X.C.)
| | - Liuding Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Y.L.); (L.W.); (X.C.)
| | - Guang Yang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China;
| | - Xiansu Chi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Y.L.); (L.W.); (X.C.)
| | - Xiao Liang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Y.L.); (L.W.); (X.C.)
| | - Yunling Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Y.L.); (L.W.); (X.C.)
| |
Collapse
|
|
21
|
Yu Q, Zhang R, Li T, Yang L, Zhou Z, Hou L, Wu W, Zhao R, Chen X, Yao Y, Huang S, Chen L. Mitochondrial Hydrogen Peroxide Activates PTEN and Inactivates Akt Leading to Autophagy Inhibition-Dependent Cell Death in Neuronal Models of Parkinson's Disease. Mol Neurobiol 2023; 60:3345-3364. [PMID: 36853430 PMCID: PMC10924433 DOI: 10.1007/s12035-023-03286-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 02/03/2023] [Indexed: 03/01/2023]
Abstract
Defective autophagy relates to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. Our recent study has demonstrated that PD toxins (6-OHDA, MPP+, or rotenone) induce neuronal apoptosis by impeding the AMPK/Akt-mTOR signaling. Here, we show that treatment with 6-OHDA, MPP+, or rotenone triggered decreases of ATG5/LC3-II and autophagosome formation with a concomitant increase of p62 in PC12, SH-SY5Y cells, and primary neurons, suggesting inhibition of autophagy. Interestingly, overexpression of wild-type ATG5 attenuated the inhibitory effect of PD toxins on autophagy, reducing neuronal apoptosis. The effects of PD toxins on autophagy and apoptosis were found to be associated with activation of PTEN and inactivation of Akt. Overexpression of dominant negative PTEN, constitutively active Akt and/or pretreatment with rapamycin rescued the cells from PD toxins-induced downregulation of ATG5/LC3-II and upregulation of p62, as well as consequential autophagosome diminishment and apoptosis in the cells. The effects of PD toxins on autophagy and apoptosis linked to excessive intracellular and mitochondrial hydrogen peroxide (H2O2) production, as evidenced by using a H2O2-scavenging enzyme catalase, a mitochondrial superoxide indicator MitoSOX and a mitochondria-selective superoxide scavenger Mito-TEMPO. Furthermore, we observed that treatment with PD toxins reduced the protein level of Parkin in the cells. Knockdown of Parkin alleviated the effects of PD toxins on H2O2 production, PTEN/Akt activity, autophagy, and apoptosis in the cells, whereas overexpression of wild-type Parkin exacerbated these effects of PD toxins, implying the involvement of Parkin in the PD toxins-induced oxidative stress. Taken together, the results indicate that PD toxins can elicit mitochondrial H2O2, which can activate PTEN and inactivate Akt leading to autophagy inhibition-dependent neuronal apoptosis, and Parkin plays a critical role in this process. Our findings suggest that co-manipulation of the PTEN/Akt/autophagy signaling by antioxidants may be exploited for the prevention of neuronal loss in PD.
Collapse
Affiliation(s)
- Qianyun Yu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
- Department of Biological Sciences, College of Science and Technology, Xinyang University, Xinyang, 464000, People's Republic of China
| | - Ruijie Zhang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
- College of Life Sciences, Anhui Medical University, Anhui, 230032, People's Republic of China
| | - Tianjing Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Liu Yang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Zhihan Zhou
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Long Hou
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Wen Wu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Rui Zhao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Xiaoling Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Yajie Yao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130-3932, USA.
- Department of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
| | - Long Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China.
| |
Collapse
|
|
22
|
Germano CA, Clemente G, Storniolo A, Romeo MA, Ferretti E, Cirone M, Di Renzo L. mTORC1/ERK1/2 Interplay Regulates Protein Synthesis and Survival in Acute Myeloid Leukemia Cell Lines. BIOLOGY 2023; 12:biology12050676. [PMID: 37237490 DOI: 10.3390/biology12050676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/22/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023]
Abstract
mTOR is constitutively activated in acute myeloid leukemia (AML) cells, as indicated by the phosphorylation of its substrates, 4EBP1 and P70S6K. Here, we found that quercetin (Q) and rapamycin (Rap) inhibited P70S6K phosphorylation, partially dephosphorylated 4EBP1, and activated ERK1/2 in U937 and THP1, two leukemia cell lines. ERK1/2 inhibition by U0126 induced a stronger dephosphorylation of mTORC1 substrates and activated AKT. The concomitant inhibition of ERK1/2 and AKT further dephosphorylated 4EBP1 and further increased Q- or Rap-mediated cytotoxicity, compared to the single ERK1/2 or AKT inhibition in cells undergoing Q- or Rap-treatments. Moreover, quercetin or rapamycin reduced autophagy, particularly when used in combination with the ERK1/2 inhibitor, U0126. This effect was not dependent on TFEB localization in nuclei or cytoplasm or on the transcription of different autophagy genes, but did correlate with the reduction in protein translation due to a strong eIF2α-Ser51 phosphorylation. Thus, ERK1/2, by limiting 4EBP1 de-phosphorylation and eIF2α phosphorylation, behaves as a paladin of protein synthesis. Based on these findings, the combined inhibition of mTORC1, ERK1/2, and AKT should be considered in treatment of AML.
Collapse
Affiliation(s)
- Concetta Anna Germano
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Giuseppe Clemente
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Antonello Storniolo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Maria Anele Romeo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Elisabetta Ferretti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Livia Di Renzo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| |
Collapse
|
|
23
|
Czegle I, Huang C, Soria PG, Purkiss DW, Shields A, Wappler-Guzzetta EA. The Role of Genetic Mutations in Mitochondrial-Driven Cancer Growth in Selected Tumors: Breast and Gynecological Malignancies. Life (Basel) 2023; 13:996. [PMID: 37109525 PMCID: PMC10145875 DOI: 10.3390/life13040996] [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: 12/28/2022] [Revised: 03/15/2023] [Accepted: 03/31/2023] [Indexed: 04/29/2023] Open
Abstract
There is an increasing understanding of the molecular and cytogenetic background of various tumors that helps us better conceptualize the pathogenesis of specific diseases. Additionally, in many cases, these molecular and cytogenetic alterations have diagnostic, prognostic, and/or therapeutic applications that are heavily used in clinical practice. Given that there is always room for improvement in cancer treatments and in cancer patient management, it is important to discover new therapeutic targets for affected individuals. In this review, we discuss mitochondrial changes in breast and gynecological (endometrial and ovarian) cancers. In addition, we review how the frequently altered genes in these diseases (BRCA1/2, HER2, PTEN, PIK3CA, CTNNB1, RAS, CTNNB1, FGFR, TP53, ARID1A, and TERT) affect the mitochondria, highlighting the possible associated individual therapeutic targets. With this approach, drugs targeting mitochondrial glucose or fatty acid metabolism, reactive oxygen species production, mitochondrial biogenesis, mtDNA transcription, mitophagy, or cell death pathways could provide further tailored treatment.
Collapse
Affiliation(s)
- Ibolya Czegle
- Department of Internal Medicine and Haematology, Semmelweis University, H-1085 Budapest, Hungary
| | - Chelsea Huang
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
| | - Priscilla Geraldine Soria
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
| | - Dylan Wesley Purkiss
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
| | - Andrea Shields
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
| | | |
Collapse
|
|
24
|
Bonello TT, Cai D, Fletcher GC, Wiengartner K, Pengilly V, Lange KS, Liu Z, Lippincott‐Schwartz J, Kavran JM, Thompson BJ. Phase separation of Hippo signalling complexes. EMBO J 2023; 42:e112863. [PMID: 36807601 PMCID: PMC10015380 DOI: 10.15252/embj.2022112863] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/12/2023] [Accepted: 01/23/2023] [Indexed: 02/22/2023] Open
Abstract
The Hippo pathway was originally discovered to control tissue growth in Drosophila and includes the Hippo kinase (Hpo; MST1/2 in mammals), scaffold protein Salvador (Sav; SAV1 in mammals) and the Warts kinase (Wts; LATS1/2 in mammals). The Hpo kinase is activated by binding to Crumbs-Expanded (Crb-Ex) and/or Merlin-Kibra (Mer-Kib) proteins at the apical domain of epithelial cells. Here we show that activation of Hpo also involves the formation of supramolecular complexes with properties of a biomolecular condensate, including concentration dependence and sensitivity to starvation, macromolecular crowding, or 1,6-hexanediol treatment. Overexpressing Ex or Kib induces formation of micron-scale Hpo condensates in the cytoplasm, rather than at the apical membrane. Several Hippo pathway components contain unstructured low-complexity domains and purified Hpo-Sav complexes undergo phase separation in vitro. Formation of Hpo condensates is conserved in human cells. We propose that apical Hpo kinase activation occurs in phase separated "signalosomes" induced by clustering of upstream pathway components.
Collapse
Affiliation(s)
- Teresa T Bonello
- EMBL Australia, John Curtin School of Medical ResearchAustralian National UniversityCanberraACTAustralia
| | - Danfeng Cai
- HHMI Janelia Research CampusAshburnVAUSA
- Department of Biochemistry and Molecular BiologyBloomberg School of Public HealthBaltimoreMDUSA
| | | | - Kyler Wiengartner
- Department of Biochemistry and Molecular BiologyBloomberg School of Public HealthBaltimoreMDUSA
| | - Victoria Pengilly
- EMBL Australia, John Curtin School of Medical ResearchAustralian National UniversityCanberraACTAustralia
| | - Kimberly S Lange
- Department of Biochemistry and Molecular BiologyBloomberg School of Public HealthBaltimoreMDUSA
| | - Zhe Liu
- HHMI Janelia Research CampusAshburnVAUSA
| | | | - Jennifer M Kavran
- Department of Biochemistry and Molecular BiologyBloomberg School of Public HealthBaltimoreMDUSA
- Department of Biophysics and Biophysical Chemistry, and Department of OncologyJohns Hopkins School of MedicineBaltimoreMDUSA
| | - Barry J Thompson
- EMBL Australia, John Curtin School of Medical ResearchAustralian National UniversityCanberraACTAustralia
- Epithelial Biology LaboratoryThe Francis Crick InstituteLondonUK
| |
Collapse
|
|
25
|
Kasprzak A. Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia. Int J Mol Sci 2023; 24:ijms24043665. [PMID: 36835075 PMCID: PMC9959216 DOI: 10.3390/ijms24043665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Along with apoptosis and inflammation, autophagy is one of three important mechanisms in CRC. The presence of autophagy/mitophagy in most normal mature intestinal epithelial cells has been confirmed, where it has mainly protective functions against reactive oxygen species (ROS)-induced DNA and protein damage. Autophagy regulates cell proliferation, metabolism, differentiation, secretion of mucins and/or anti-microbial peptides. Abnormal autophagy in intestinal epithelial cells leads to dysbiosis, a decline in local immunity and a decrease in cell secretory function. The insulin-like growth factor (IGF) signaling pathway plays an important role in colorectal carcinogenesis. This is evidenced by the biological activities of IGFs (IGF-1 and IGF-2), IGF-1 receptor type 1 (IGF-1R) and IGF-binding proteins (IGF BPs), which have been reported to regulate cell survival, proliferation, differentiation and apoptosis. Defects in autophagy are found in patients with metabolic syndrome (MetS), inflammatory bowel diseases (IBD) and CRC. In neoplastic cells, the IGF system modulates the autophagy process bidirectionally. In the current era of improving CRC therapies, it seems important to investigate the exact mechanisms not only of apoptosis, but also of autophagy in different populations of tumor microenvironment (TME) cells. The role of the IGF system in autophagy in normal as well as transformed colorectal cells still seems poorly understood. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.
Collapse
Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
| |
Collapse
|
|
26
|
Li J, Chen H, Cai L, Guo D, Zhang D, Zhou X, Xie J. SDF-1α Promotes Chondrocyte Autophagy through CXCR4/mTOR Signaling Axis. Int J Mol Sci 2023; 24:1710. [PMID: 36675225 PMCID: PMC9867011 DOI: 10.3390/ijms24021710] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
SDF-1α, the most common isoform of stromal cell-derived factor 1, has shown vital effects in regulating chondrocyte proliferation, maturation, and chondrogenesis. Autophagy is a highly conserved biological process to help chondrocytes survive in harsh environments. However, the effect of SDF-1α on chondrocyte autophagy is still unknown. This study aims to investigate the effect of SDF-1α on chondrocyte autophagy and the underlying biomechanism. Transmission electron microscope assays and mRFP-GFP-LC3 adenovirus double label transfection assays were performed to detect the autophagic flux of chondrocytes. Western blots and immunofluorescence staining assays were used to detect the expression of autophagy-related proteins in chondrocytes. RNA sequencing and qPCR were conducted to assess changes in autophagy-related mRNA expression. SDF-1α upregulated the number of autophagosomes and autolysosomes in chondrocytes. It also increased the expression of autophagy-related proteins including ULK-1, Beclin-1 and LC3B, and decreased the expression of p62, an autophagy substrate protein. SDF-1α-mediated autophagy of chondrocytes required the participation of receptor CXCR4. Moreover, SDF-1α-enhanced autophagy of chondrocytes was through the inhibition of phosphorylation of mTOR signaling on the upstream of autophagy. Knockdown by siRNA and inhibition by signaling inhibitor further confirmed the importance of the CXCR4/mTOR signaling axis in SDF-1α-induced autophagy of chondrocytes. For the first time, this study elucidated that SDF-1α promotes chondrocyte autophagy through the CXCR4/mTOR signaling axis.
Collapse
Affiliation(s)
- Jiazhou Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Hao Chen
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Lang Cai
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Daimo Guo
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Demao Zhang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Jing Xie
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
27
|
Netherton CL, Shimmon GL, Hui JYK, Connell S, Reis AL. African Swine Fever Virus Host-Pathogen Interactions. Subcell Biochem 2023; 106:283-331. [PMID: 38159232 DOI: 10.1007/978-3-031-40086-5_11] [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] [Indexed: 01/03/2024]
Abstract
African swine fever virus is a complex double-stranded DNA virus that exhibits tropism for cells of the mononuclear phagocytic system. Virus replication is a multi-step process that involves the nucleus of the host cell as well the formation of large perinuclear sites where progeny virions are assembled prior to transport to, and budding through, the plasma membrane. Like many viruses, African swine fever virus reorganises the cellular architecture to facilitate its replication and has evolved multiple mechanisms to avoid the potential deleterious effects of host cell stress response pathways. However, how viral proteins and virus-induced structures trigger cellular stress pathways and manipulate the subsequent responses is still relatively poorly understood. African swine fever virus alters nuclear substructures, modulates autophagy, apoptosis and the endoplasmic reticulum stress response pathways. The viral genome encodes for at least 150 genes, of which approximately 70 are incorporated into the virion. Many of the non-structural genes have not been fully characterised and likely play a role in host range and modifying immune responses. As the field moves towards approaches that take a broader view of the effect of expression of individual African swine fever genes, we summarise how the different steps in virus replication interact with the host cell and the current state of knowledge on how it modulates the resulting stress responses.
Collapse
|
|
28
|
Morleo M, Vieira HL, Pennekamp P, Palma A, Bento-Lopes L, Omran H, Lopes SS, Barral DC, Franco B. Crosstalk between cilia and autophagy: implication for human diseases. Autophagy 2023; 19:24-43. [PMID: 35613303 PMCID: PMC9809938 DOI: 10.1080/15548627.2022.2067383] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Macroautophagy/autophagy is a self-degradative process necessary for cells to maintain their energy balance during development and in response to nutrient deprivation. Autophagic processes are tightly regulated and have been found to be dysfunctional in several pathologies. Increasing experimental evidence points to the existence of an interplay between autophagy and cilia. Cilia are microtubule-based organelles protruding from the cell surface of mammalian cells that perform a variety of motile and sensory functions and, when dysfunctional, result in disorders known as ciliopathies. Indeed, selective autophagic degradation of ciliary proteins has been shown to control ciliogenesis and, conversely, cilia have been reported to control autophagy. Moreover, a growing number of players such as lysosomal and mitochondrial proteins are emerging as actors of the cilia-autophagy interplay. However, some of the published data on the cilia-autophagy axis are contradictory and indicate that we are just starting to understand the underlying molecular mechanisms. In this review, the current knowledge about this axis and challenges are discussed, as well as the implication for ciliopathies and autophagy-associated disorders.
Collapse
Affiliation(s)
- Manuela Morleo
- Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy,Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Helena L.A. Vieira
- CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, Portugal,UCIBIO, Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica, Portugal,Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica, Portugal
| | - Petra Pennekamp
- Department of General Pediatrics, University Hospital Münster, University of Münster, Münster48149, Germany,Member of the European Reference Networks ERN-LUNG, Lisbon, Portugal
| | - Alessandro Palma
- Department of Onco-hematology, Gene and Cell Therapy, Bambino Gesù Children’s Hospital - IRCCS, Rome, Italy
| | - Liliana Bento-Lopes
- CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, Portugal
| | - Heymut Omran
- Department of General Pediatrics, University Hospital Münster, University of Münster, Münster48149, Germany,Member of the European Reference Networks ERN-LUNG, Lisbon, Portugal
| | - Susana S. Lopes
- CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, Portugal,Member of the European Reference Networks ERN-LUNG, Lisbon, Portugal
| | - Duarte C. Barral
- CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, Portugal
| | - Brunella Franco
- Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy,Medical Genetics, Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy,Scuola Superiore Meridionale, School for Advanced Studies, Naples, Italy,CONTACT Brunella Franco CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, Lisboa1169-056, Portugal
| |
Collapse
|
|
29
|
Nokhostin F, Azadehrah M, Azadehrah M. The multifaced role and therapeutic regulation of autophagy in ovarian cancer. Clin Transl Oncol 2022; 25:1207-1217. [PMID: 36534371 DOI: 10.1007/s12094-022-03045-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
Ovarian cancer (OC) is one of the tumors that occurs most frequently in women. Autophagy is involved in cell homeostasis, biomolecule recycling, and survival, making it a potential target for anti-tumor drugs. It is worth noting that growing evidence reveals a close link between autophagy and OC. In the context of OC, autophagy demonstrates activity as both a tumor suppressor and a tumor promoter, depending on the context. Autophagy's exact function in OC is greatly reliant on the tumor microenvironment (TME) and other conditions, such as hypoxia, nutritional deficiency, chemotherapy, and so on. However, what can be concluded from different studies is that autophagy-related signaling pathways, especially PI3K/AKT/mTOR axis, increase in advanced stages and malignant phenotype of the disease reduces autophagy and ultimately leads to tumor progression. This study sought to present a thorough understanding of the role of autophagy-related signaling pathways in OC and existing therapies targeting these signaling pathways.
Collapse
Affiliation(s)
- Fahimeh Nokhostin
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shahid Sadughi University of Medical Sciences, Yazd, Iran
| | - Mahboobeh Azadehrah
- Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Malihe Azadehrah
- Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| |
Collapse
|
|
30
|
Immunomodulatory and anti-inflammatory and anticancer activities of porphyran, a sulfated galactan. Carbohydr Polym 2022; 301:120326. [DOI: 10.1016/j.carbpol.2022.120326] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/28/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
|
|
31
|
Alfonso-Pérez T, Baonza G, Herranz G, Martín-Belmonte F. Deciphering the interplay between autophagy and polarity in epithelial tubulogenesis. Semin Cell Dev Biol 2022; 131:160-172. [PMID: 35641407 DOI: 10.1016/j.semcdb.2022.05.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 12/14/2022]
Abstract
The Metazoan complexity arises from a primary building block, the epithelium, which comprises a layer of polarized cells that divide the organism into compartments. Most of these body compartments are organs formed by epithelial tubes that enclose an internal hollow space or lumen. Over the last decades, multiple studies have unmasked the paramount events required to form this lumen de novo. In epithelial cells, these events mainly involve recognizing external clues, establishing and maintaining apicobasal polarity, endo-lysosomal trafficking, and expanding the created lumen. Although canonical autophagy has been classically considered a catabolic process needed for cell survival, multiple studies have also emphasized its crucial role in epithelial polarity, morphogenesis and cellular homeostasis. Furthermore, non-canonical autophagy pathways have been recently discovered as atypical secretory routes. Both canonical and non-canonical pathways play essential roles in epithelial polarity and lumen formation. This review addresses how the molecular machinery for epithelial polarity and autophagy interplay in different processes and how autophagy functions influence lumenogenesis, emphasizing its role in the lumen formation key events.
Collapse
Affiliation(s)
- Tatiana Alfonso-Pérez
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo, Ochoa", CSIC-UAM, Madrid 28049, Spain; Ramon & Cajal Health Research Institute (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid 28034, Spain
| | - Gabriel Baonza
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo, Ochoa", CSIC-UAM, Madrid 28049, Spain
| | - Gonzalo Herranz
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo, Ochoa", CSIC-UAM, Madrid 28049, Spain; Ramon & Cajal Health Research Institute (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid 28034, Spain
| | - Fernando Martín-Belmonte
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo, Ochoa", CSIC-UAM, Madrid 28049, Spain; Ramon & Cajal Health Research Institute (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid 28034, Spain.
| |
Collapse
|
|
32
|
Hu T, Gong H, Xu J, Huang Y, Wu F, He Z. Nanomedicines for Overcoming Cancer Drug Resistance. Pharmaceutics 2022; 14:pharmaceutics14081606. [PMID: 36015232 PMCID: PMC9412887 DOI: 10.3390/pharmaceutics14081606] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/25/2022] Open
Abstract
Clinically, cancer drug resistance to chemotherapy, targeted therapy or immunotherapy remains the main impediment towards curative cancer therapy, which leads directly to treatment failure along with extended hospital stays, increased medical costs and high mortality. Therefore, increasing attention has been paid to nanotechnology-based delivery systems for overcoming drug resistance in cancer. In this respect, novel tumor-targeting nanomedicines offer fairly effective therapeutic strategies for surmounting the various limitations of chemotherapy, targeted therapy and immunotherapy, enabling more precise cancer treatment, more convenient monitoring of treatment agents, as well as surmounting cancer drug resistance, including multidrug resistance (MDR). Nanotechnology-based delivery systems, including liposomes, polymer micelles, nanoparticles (NPs), and DNA nanostructures, enable a large number of properly designed therapeutic nanomedicines. In this paper, we review the different mechanisms of cancer drug resistance to chemotherapy, targeted therapy and immunotherapy, and discuss the latest developments in nanomedicines for overcoming cancer drug resistance.
Collapse
Affiliation(s)
- Tingting Hu
- Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; (T.H.); (J.X.); (Y.H.)
| | - Hanlin Gong
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Jiayue Xu
- Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; (T.H.); (J.X.); (Y.H.)
| | - Yuan Huang
- Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; (T.H.); (J.X.); (Y.H.)
| | - Fengbo Wu
- Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; (T.H.); (J.X.); (Y.H.)
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
- Correspondence: (F.W.); or (Z.H.); Tel.: +86-28-85422965 (Z.H.); Fax: +86-28-85422664 (Z.H.)
| | - Zhiyao He
- Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; (T.H.); (J.X.); (Y.H.)
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
- Correspondence: (F.W.); or (Z.H.); Tel.: +86-28-85422965 (Z.H.); Fax: +86-28-85422664 (Z.H.)
| |
Collapse
|
|
33
|
The cross-talk of autophagy and apoptosis in breast carcinoma: implications for novel therapies? Biochem J 2022; 479:1581-1608. [PMID: 35904454 DOI: 10.1042/bcj20210676] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 12/12/2022]
Abstract
Breast cancer is still the most common cancer in women worldwide. Resistance to drugs and recurrence of the disease are two leading causes of failure in treatment. For a more efficient treatment of patients, the development of novel therapeutic regimes is needed. Recent studies indicate that modulation of autophagy in concert with apoptosis induction may provide a promising novel strategy in breast cancer treatment. Apoptosis and autophagy are two tightly regulated distinct cellular processes. To maintain tissue homeostasis abnormal cells are disposed largely by means of apoptosis. Autophagy, however, contributes to tissue homeostasis and cell fitness by scavenging of damaged organelles, lipids, proteins, and DNA. Defects in autophagy promote tumorigenesis, whereas upon tumor formation rapidly proliferating cancer cells may rely on autophagy to survive. Given that evasion of apoptosis is one of the characteristic hallmarks of cancer cells, inhibiting autophagy and promoting apoptosis can negatively influence cancer cell survival and increase cell death. Hence, combination of antiautophagic agents with the enhancement of apoptosis may restore apoptosis and provide a therapeutic advantage against breast cancer. In this review, we discuss the cross-talk of autophagy and apoptosis and the diverse facets of autophagy in breast cancer cells leading to novel models for more effective therapeutic strategies.
Collapse
|
|
34
|
Zhang S, Zhu N, Gu J, Li HF, Qiu Y, Liao DF, Qin L. Crosstalk between Lipid Rafts and Aging: New Frontiers for Delaying Aging. Aging Dis 2022; 13:1042-1055. [PMID: 35855333 PMCID: PMC9286918 DOI: 10.14336/ad.2022.0116] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/16/2022] [Indexed: 12/15/2022] Open
Abstract
With the rapid aging in the global population, delay of aging has become a hot research topic. Lipid rafts (LRs) are microdomains in the plasma membrane that contain sphingolipids and cholesterol. Emerging evidence indicates an interesting interplay between LRs and aging. LRs and their components are altered with aging. Further, the aging process is strongly influenced by LRs. In recent years, LRs and their component signaling molecules have been recognized to affect aging by interfering with its hallmarks. Therefore, targeting LRs is a promising strategy to delay aging.
Collapse
Affiliation(s)
- Shuo Zhang
- 1Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Neng Zhu
- 2Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Jia Gu
- 1Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Hong-Fang Li
- 1Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Yun Qiu
- 1Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Duan-Fang Liao
- 1Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Li Qin
- 1Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.,3Hunan Province Engineering Research Center of Bioactive Substance Discovery of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| |
Collapse
|
|
35
|
Eldeeb MA, Esmaili M, Hassan M, Ragheb MA. The Role of PTEN-L in Modulating PINK1-Parkin-Mediated Mitophagy. Neurotox Res 2022; 40:1103-1114. [PMID: 35699891 DOI: 10.1007/s12640-022-00475-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 12/27/2021] [Accepted: 01/13/2022] [Indexed: 11/24/2022]
Abstract
An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, human cells have evolved sophisticated quality control mechanisms to identify and eliminate abnormal dysfunctional mitochondria. One pivotal mitochondrial quality control pathway is PINK1/Parkin-dependent mitophagy which mediates the selective removal of the dysfunctional mitochondria from the cell by autophagy. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial Ser/Thr kinase that was originally identified as a gene responsible for autosomal recessive early-onset Parkinson's disease (PD). Notably, upon failure of mitochondrial import, Parkin, another autosomal-recessive PD gene, is recruited to mitochondria and mediates the autophagic clearance of deregulated mitochondria. Importantly, recruitment of Parkin to damaged mitochondria hinges on the accumulation of PINK1 on the outer mitochondrial membrane (OMM). Normally, PINK1 is imported from the cytosol through the translocase of the outer membrane (TOM) complex, a large multimeric channel responsible for the import of most mitochondrial proteins. After import, PINK1 is rapidly degraded. Thus, at steady-state, PINK1 levels are kept low. However, upon mitochondrial import failure, PINK1 accumulates and forms a high-molecular weight > 700 kDa complex with TOM on the OMM. Thus, PINK1 functions as sensor, tagging dysfunctional mitochondria for Parkin-mediated mitophagy. Although much has been learned about the function of PINK1 in mitophagy, the biochemical and structural basis of negative regulation of PINK1 operation and functions is far from clear. Recent work unveiled new players as PTEN-l as negative regulator of PINK1 function. Herein, we review key aspects of mitophagy and PINK1/Parkin-mediated mitophagy with highlighting the role of negative regulation of PINK1 function and presenting some of the key future directions in PD cell biology.
Collapse
Affiliation(s)
- Mohamed A Eldeeb
- Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, QC, Canada. .,Department of Chemistry, Biochemistry Division, Cairo University, Giza, Egypt.
| | - Mansoore Esmaili
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Marwa Hassan
- Department of Chemistry, Biochemistry Division, Cairo University, Giza, Egypt
| | - Mohamed A Ragheb
- Department of Chemistry, Biochemistry Division, Cairo University, Giza, Egypt
| |
Collapse
|
|
36
|
The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis. Int J Mol Sci 2022; 23:ijms23105694. [PMID: 35628504 PMCID: PMC9143529 DOI: 10.3390/ijms23105694] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/13/2022] [Accepted: 05/15/2022] [Indexed: 12/10/2022] Open
Abstract
Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.
Collapse
|
|
37
|
Gatica D, Chiong M, Lavandero S, Klionsky DJ. The role of autophagy in cardiovascular pathology. Cardiovasc Res 2022; 118:934-950. [PMID: 33956077 PMCID: PMC8930074 DOI: 10.1093/cvr/cvab158] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/30/2021] [Indexed: 12/11/2022] Open
Abstract
Macroautophagy/autophagy is a conserved catabolic recycling pathway in which cytoplasmic components are sequestered, degraded, and recycled to survive various stress conditions. Autophagy dysregulation has been observed and linked with the development and progression of several pathologies, including cardiovascular diseases, the leading cause of death in the developed world. In this review, we aim to provide a broad understanding of the different molecular factors that govern autophagy regulation and how these mechanisms are involved in the development of specific cardiovascular pathologies, including ischemic and reperfusion injury, myocardial infarction, cardiac hypertrophy, cardiac remodelling, and heart failure.
Collapse
Affiliation(s)
- Damián Gatica
- Department of Molecular, Cellular and Developmental Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Ave, Ann Arbor, MI 48109-2216, USA
| | - Mario Chiong
- Department of Biochemistry and Molecular Biology, Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Olivos 1007, Independencia, Santiago 8380492, Chile
| | - Sergio Lavandero
- Department of Biochemistry and Molecular Biology, Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Olivos 1007, Independencia, Santiago 8380492, Chile
- Corporación Centro de Estudios Científicos de las Enfermedades Crónicas (CECEC), 926 JF Gonzalez, Santiago 7860201, Chile
- Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8573, USA
| | - Daniel J Klionsky
- Department of Molecular, Cellular and Developmental Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Ave, Ann Arbor, MI 48109-2216, USA
| |
Collapse
|
|
38
|
Belyaeva E, Kharwar RK, Ulasov IV, Karlina I, Timashev P, Mohammadinejad R, Acharya A. Isoforms of autophagy-related proteins: role in glioma progression and therapy resistance. Mol Cell Biochem 2022; 477:593-604. [PMID: 34854022 DOI: 10.1007/s11010-021-04308-w] [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: 08/04/2021] [Accepted: 11/19/2021] [Indexed: 11/26/2022]
Abstract
Autophagy is the process of recycling and utilization of degraded organelles and macromolecules in the cell compartments formed during the fusion of autophagosomes with lysosomes. During autophagy induction the healthy and tumor cells adapt themselves to harsh conditions such as cellular stress or insufficient supply of nutrients in the cell environment to maintain their homeostasis. Autophagy is currently seen as a form of programmed cell death along with apoptosis and necroptosis. In recent years multiple studies have considered the autophagy as a potential mechanism of anticancer therapy in malignant glioma. Although, subsequent steps in autophagy development are known and well-described, on molecular level the mechanism of autophagosome initiation and maturation using autophagy-related proteins is under investigation. This article reviews current state about the mechanism of autophagy, its molecular pathways and the most recent studies on roles of autophagy-related proteins and their isoforms in glioma progression and its treatment.
Collapse
Affiliation(s)
- Elizaveta Belyaeva
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, Russia, 119991
| | - Rajesh Kumar Kharwar
- Endocrine Research Laboratory, Department of Zoology, Kutir Post Graduate College, Chakkey, Jaunpur, UP, India
| | - Ilya V Ulasov
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, Russia, 119991.
| | - Irina Karlina
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, Russia, 119991
| | - Petr Timashev
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation, 119991
- Department of Polymers and Composites, N.N.Semenov Institute of Chemical Physics, 4 Kosygin st., Moscow, Russian Federation, 119991
- Chemistry Department, Lomonosov Moscow State University, Leninskiye Gory 1-3, Moscow, Russian Federation, 119991
| | - Reza Mohammadinejad
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Arbind Acharya
- Tumor Immunology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, UP, 221005, India.
| |
Collapse
|
|
39
|
Bata N, Cosford NDP. Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics. ACS Pharmacol Transl Sci 2021; 4:1728-1746. [PMID: 34927007 DOI: 10.1021/acsptsci.1c00130] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Indexed: 12/25/2022]
Abstract
Autophagy and apoptosis are functionally distinct mechanisms for cytoplasmic and cellular turnover. While these two pathways are distinct, they can also regulate each other, and central components of the apoptosis or autophagy pathway regulate both processes directly. Furthermore, several upstream stress-inducing signaling pathways can influence both autophagy and apoptosis. The crosstalk between autophagy and apoptosis has an integral role in pathological processes, including those related to cancer, homeostasis, and aging. Apoptosis is a form of programmed cell death, tightly regulated by various cellular and biochemical mechanisms, some of which have been the focus of drug discovery efforts targeting cancer therapeutics. Autophagy is a cellular degradation pathway whereby cells recycle macromolecules and organelles to generate energy when subjected to stress. Autophagy can act as either a prodeath or a prosurvival process and is both tissue and microenvironment specific. In this review we describe five groups of proteins that are integral to the apoptosis pathway and discuss their role in regulating autophagy. We highlight several apoptosis-inducing small molecules and biologics that have been developed and advanced into the clinic and discuss their effects on autophagy. For the most part, these apoptosis-inducing compounds appear to elevate autophagy activity. Under certain circumstances autophagy demonstrates cytoprotective functions and is overactivated in response to chemo- or radiotherapy which can lead to drug resistance, representing a clinical obstacle for successful cancer treatment. Thus, targeting the autophagy pathway in combination with apoptosis-inducing compounds may be a promising strategy for cancer therapy.
Collapse
Affiliation(s)
- Nicole Bata
- Cell and Molecular Biology of Cancer Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Nicholas D P Cosford
- Cell and Molecular Biology of Cancer Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States
| |
Collapse
|
|
40
|
The two faces of autophagy in oral squamous cell carcinoma. Arch Oral Biol 2021; 134:105321. [PMID: 34923284 DOI: 10.1016/j.archoralbio.2021.105321] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To undertake a comprehensive review of the current knowledge and understanding of autophagy in oral squamous cell carcinoma (OSCC), focusing on putative roles in tumour suppression and survival along with the influence of this cell death pathway on the development of resistance to chemotherapeutic treatment. DESIGN Several well utilised databases (PubMed, Medline, Google Scholar) were searched for the relevant literature using terms and keywords including but not limited too; autophagy and cancer, autophagy and OSCC, tumour survival, autophagy and oral microbiome, autophagy immunogenicity, OSCC chemoresistance. RESULTS Up-regulation of autophagy has been shown to promote tumour cell survival in the tumour microenvironment while in healthy cells, autophagy induction acts to prevent severe DNA mutations that can lead to cancer. Cancers utilise the autophagy pathway to promote survival during the stress of chemotherapeutic treatment and can induce resistance to chemotherapeutic drugs CONCLUSION: The ambiguous role of autophagy within cancers is still problematic in clinical fields. Within OSCC understanding whether autophagy plays a preventive or causative role is essential and may be beneficial in determining how modulation of this pathway may impact on OSSC and oral cancer patients.
Collapse
|
|
41
|
Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy. Int J Mol Sci 2021; 22:ijms222212466. [PMID: 34830349 PMCID: PMC8618802 DOI: 10.3390/ijms222212466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 01/18/2023] Open
Abstract
Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings.
Collapse
|
|
42
|
ROS Pleiotropy in Melanoma and Local Therapy with Physical Modalities. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6816214. [PMID: 34777692 PMCID: PMC8580636 DOI: 10.1155/2021/6816214] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/06/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Metabolic energy production naturally generates unwanted products such as reactive oxygen species (ROS), causing oxidative damage. Oxidative damage has been linked to several pathologies, including diabetes, premature aging, neurodegenerative diseases, and cancer. ROS were therefore originally anticipated as an imperative evil, a product of an imperfect system. More recently, however, the role of ROS in signaling and tumor treatment is increasingly acknowledged. This review addresses the main types, sources, and pathways of ROS in melanoma by linking their pleiotropic roles in antioxidant and oxidant regulation, hypoxia, metabolism, and cell death. In addition, the implications of ROS in various physical therapy modalities targeting melanoma, such as radiotherapy, electrochemotherapy, hyperthermia, photodynamic therapy, and medical gas plasma, are also discussed. By including ROS in the main picture of melanoma skin cancer and as an integral part of cancer therapies, a greater understanding of melanoma cell biology is presented, which ultimately may elucidate additional clues on targeting therapy resistance of this most deadly form of skin cancer.
Collapse
|
|
43
|
Benitez JA, Finlay D, Castanza A, Parisian AD, Ma J, Longobardi C, Campos A, Vadla R, Izurieta A, Scerra G, Koga T, Long T, Chavez L, Mesirov JP, Vuori K, Furnari F. PTEN deficiency leads to proteasome addiction: a novel vulnerability in glioblastoma. Neuro Oncol 2021; 23:1072-1086. [PMID: 33428749 DOI: 10.1093/neuonc/noab001] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of approximately 15 months; therefore, more effective treatment options for GBM are required. To identify new drugs targeting GBMs, we performed a high-throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype. METHODS High-throughput drug screening was performed on GSCs followed by a dose-response assay of the 5 identified original "hits." A PI3K/mTOR dependency to a proteasome inhibitor (carfilzomib), was confirmed by genetic and pharmacologic experiments. Proteasome Inhibition Response Signatures were derived from proteomic and bioinformatic analysis. Molecular mechanism of action was determined using three-dimensional (3D) GBM-organoids and preclinical orthotopic models. RESULTS We found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in 3D GBM-organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PI3K/mTOR pathway occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition. CONCLUSIONS Proteasome inhibition is a potential synthetic lethal therapeutic strategy for GBM with proteasome addiction due to a high protein synthesis rate and autophagy deficiency.
Collapse
Affiliation(s)
- Jorge A Benitez
- Ludwig Cancer Research, University of California at San Diego, La Jolla, California.,Bristol-Myers Squibb, San Diego, California
| | - Darren Finlay
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Anthony Castanza
- Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, California
| | - Alison D Parisian
- Ludwig Cancer Research, University of California at San Diego, La Jolla, California.,Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, California
| | - Jianhui Ma
- Ludwig Cancer Research, University of California at San Diego, La Jolla, California
| | - Ciro Longobardi
- Department of Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Alex Campos
- Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, California.,Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Raghavendra Vadla
- Ludwig Cancer Research, University of California at San Diego, La Jolla, California
| | - Alejandro Izurieta
- Ludwig Cancer Research, University of California at San Diego, La Jolla, California
| | - Gianluca Scerra
- Department of Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Tomoyuki Koga
- Ludwig Cancer Research, University of California at San Diego, La Jolla, California.,Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota
| | - Tao Long
- Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, California.,Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Lukas Chavez
- Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, California
| | - Jill P Mesirov
- Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, California
| | - Kristiina Vuori
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Frank Furnari
- Ludwig Cancer Research, University of California at San Diego, La Jolla, California.,Department of Pathology, University of California at San Diego, La Jolla, California
| |
Collapse
|
|
44
|
Cui Y, Zhang S, Miao C, Liang C, Chen X, Yan T, Bu H, Dong H, Li J, Li J, Wang Z, Liu B. Identification of autophagy-related long non-coding RNA prognostic and immune signature for clear cell renal cell carcinoma. Transl Androl Urol 2021; 10:3317-3331. [PMID: 34532256 PMCID: PMC8421821 DOI: 10.21037/tau-21-278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 07/02/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Studies over the past decade have shown that long non-coding RNAs (lncRNAs) play an essential role in the tumorigenesis and progression of kidney renal clear cell carcinoma (KIRC). Meanwhile, autophagy has been demonstrated to regulate KIRC pathogenesis and targeting therapy resistance. However, the prognostic value of autophagy-related lncRNAs in KIRC patients has not been reported before. METHODS In this study, we obtained transcriptome data of 611 KIRC cases from the TCGA database and 258 autophagy-related mRNAs from the HADb database to identify autophagy-related lncRNAs by co-expression network. A prognostic model was then established basing on these autophagy-related lncRNAs, dividing patients into high-risk and low-risk groups. Survival analysis, clinical variables dependent receiver operating characteristic (ROC) analyses, univariate/multivariate Cox analyses, and clinical correlation analysis were performed based on risk signature with R language. Gene set enrichment analysis (GSEA) was then performed to investigate the potential mechanism of the risk signature promoting KIRC progression with GSEA software. CIBERSORT algorithm was performed to assess the impact of these lncRNAs on the infiltration of immune cells. RESULTS A total of 17 lncRNAs were screened out and all these lncRNAs were found significantly related to KIRC patients' overall survival in subsequent survival analyses. Besides, the overall survival time in the high-risk group was much poorer than in the low-risk group. The ROC analysis revealed that the prognostic value of risk signature was better than age, gender, grade, and N stage. Univariate/multivariate analyses suggested that the risk signature was an independent predictive factor for KIRC patients. Immune and autophagy related pathways were dramatically enriched in high-risk and low-risk groups, respectively, and lncRNAs related immune cells were identified by CIBERSORT. CONCLUSIONS In summary, our identified 17 autophagy-related lncRNAs had prognostic value for KIRC patients which may function in immunomodulation.
Collapse
Affiliation(s)
- Yankang Cui
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shaobo Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chenkui Miao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chao Liang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaochao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Yan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hengtao Bu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huiyu Dong
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Junchen Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zengjun Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bianjiang Liu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
45
|
Autophagy Inhibition in BRAF-Driven Cancers. Cancers (Basel) 2021; 13:cancers13143498. [PMID: 34298710 PMCID: PMC8306561 DOI: 10.3390/cancers13143498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/10/2021] [Accepted: 07/11/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary BRAF is a protein kinase that is frequently mutationally activated in cancer. Mutant BRAF can be pharmacologically inhibited, which in combination with blockade of its direct effector, MEK1/2, is an FDA-approved therapeutic strategy for several BRAF-mutated cancer patients, such as melanoma, non-small-cell lung carcinoma, and thyroid cancer. However, therapy resistance is a major clinical challenge, highlighting the need for comprehensive investigations on the biological causes of such resistance, as well as to develop novel therapeutic strategies to improve patient survival. Autophagy is a cellular recycling process, which has been shown to allow cancer cells to escape from BRAF inhibition. Combined blockade of autophagy and BRAF signaling is a novel therapeutic strategy that is currently being tested in clinical trials. This review describes the relationship between BRAF-targeted therapy and autophagy regulation and discusses possible future treatment strategies. Abstract Several BRAF-driven cancers, including advanced BRAFV600E/K-driven melanoma, non-small-cell lung carcinoma, and thyroid cancer, are currently treated using first-line inhibitor combinations of BRAFV600E plus MEK1/2. However, despite the success of this vertical inhibition strategy, the durability of patient response is often limited by the phenomenon of primary or acquired drug resistance. It has recently been shown that autophagy, a conserved cellular recycling process, is increased in BRAF-driven melanoma upon inhibition of BRAFV600E signaling. Autophagy is believed to promote tumor progression of established tumors and also to protect cancer cells from the cytotoxic effects of chemotherapy. To this end, BRAF inhibitor (BRAFi)-resistant cells often display increased autophagy compared to responsive lines. Several mechanisms have been proposed for BRAFi-induced autophagy, such as activation of the endoplasmic reticulum (ER) stress gatekeeper GRP78, AMP-activated protein kinase, and transcriptional regulation of the autophagy regulating transcription factors TFEB and TFE3 via ERK1/2 or mTOR inhibition. This review describes the relationship between BRAF-targeted therapy and autophagy regulation, and discusses possible future treatment strategies of combined inhibition of oncogenic signaling plus autophagy for BRAF-driven cancers.
Collapse
|
|
46
|
Lin YX, Wang Y, Ding J, Jiang A, Wang J, Yu M, Blake S, Liu S, Bieberich CJ, Farokhzad OC, Mei L, Wang H, Shi J. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models. Sci Transl Med 2021; 13:13/599/eaba9772. [PMID: 34162754 DOI: 10.1126/scitranslmed.aba9772] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 12/29/2020] [Accepted: 05/17/2021] [Indexed: 12/12/2022]
Abstract
Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor's sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma cells and Pten-null prostate cancer cells, which in turn induces autophagy and triggers cell death-associated immune activation via release of damage-associated molecular patterns. In vivo results illustrated that PTEN mRNA nanoparticles can reverse the immunosuppressive TME by promoting CD8+ T cell infiltration of the tumor tissue, enhancing the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reducing regulatory T cells and myeloid-derived suppressor cells. The combination of PTEN mRNA nanoparticles with an immune checkpoint inhibitor, anti-programmed death-1 antibody, results in a highly potent antitumor effect in a subcutaneous model of Pten-mutated melanoma and an orthotopic model of Pten-null prostate cancer. Moreover, the combinatorial treatment elicits immunological memory in the Pten-null prostate cancer model.
Collapse
Affiliation(s)
- Yao-Xin Lin
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yi Wang
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,CAS Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China.,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianxun Ding
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Aiping Jiang
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jie Wang
- CAS Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China.,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mian Yu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Sara Blake
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - Shuaishuai Liu
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250 USA
| | - Charles J Bieberich
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250 USA.,University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Omid C Farokhzad
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Lin Mei
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Guangzhou, Guangdong 510006, China. .,Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Hao Wang
- CAS Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China. .,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jinjun Shi
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| |
Collapse
|
|
47
|
Zada S, Hwang JS, Ahmed M, Lai TH, Pham TM, Elashkar O, Kim DR. Cross talk between autophagy and oncogenic signaling pathways and implications for cancer therapy. Biochim Biophys Acta Rev Cancer 2021; 1876:188565. [PMID: 33992723 DOI: 10.1016/j.bbcan.2021.188565] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/05/2021] [Accepted: 05/08/2021] [Indexed: 02/07/2023]
Abstract
Autophagy is a highly conserved metabolic process involved in the degradation of intracellular components including proteins and organelles. Consequently, it plays a critical role in recycling metabolic energy for the maintenance of cellular homeostasis in response to various stressors. In cancer, autophagy either suppresses or promotes cancer progression depending on the stage and cancer type. Epithelial-mesenchymal transition (EMT) and cancer metastasis are directly mediated by oncogenic signal proteins including SNAI1, SLUG, ZEB1/2, and NOTCH1, which are functionally correlated with autophagy. In this report, we discuss the crosstalk between oncogenic signaling pathways and autophagy followed by possible strategies for cancer treatment via regulation of autophagy. Although autophagy affects EMT and cancer metastasis, the overall signaling pathways connecting cancer progression and autophagy are still illusive. In general, autophagy plays a critical role in cancer cell survival by providing a minimum level of energy via self-digestion. Thus, cancer cells face nutrient limitations and challenges under stress during EMT and metastasis. Conversely, autophagy acts as a potential cancer suppressor by degrading oncogenic proteins, which are essential for cancer progression, and by removing damaged components such as mitochondria to enhance genomic stability. Therefore, autophagy activators or inhibitors represent possible cancer therapeutics. We further discuss the regulation of autophagy-dependent degradation of oncogenic proteins and its functional correlation with oncogenic signaling pathways, with potential applications in cancer therapy.
Collapse
Affiliation(s)
- Sahib Zada
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Jin Seok Hwang
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Mahmoud Ahmed
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Trang Huyen Lai
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Trang Minh Pham
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Omar Elashkar
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea.
| |
Collapse
|
|
48
|
Mohammadi E, Sadoughi F, Younesi S, Karimian A, Asemi Z, Farsad-Akhtar N, Jahanbakhshi F, Jamilian H, Yousefi B. The molecular mechanism of nuclear signaling for degradation of cytoplasmic DNA: Importance in DNA damage response and cancer. DNA Repair (Amst) 2021; 103:103115. [PMID: 33915415 DOI: 10.1016/j.dnarep.2021.103115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/03/2021] [Accepted: 04/04/2021] [Indexed: 11/17/2022]
Abstract
This review summarizes and addresses non-coding RNAs (rRNA, tRNA, Vault and Y RNA, snRNA, and miRNA) cytoplasmic decay pathways, the molecules, enzymes, and modifications such as uridylation, which play vital roles in the degradation processes in various eukaryotic organisms. Plus, SIRT1's role in fundamental cellular processes, including autophagy, DNA repair, DNA damage response (DDR), and the molecular mechanisms, is explored. Further, the HuR (an RNA-binding protein) impact on the expression of genes following DNA damage, and the pathways that regulate HuR function, which is through phosphorylation by Chk1/Cdk1 and Chk2, are specified. Finally, the role of DIF1/ Rnr2-Rnr4 in DDR has been discussed.
Collapse
Affiliation(s)
- Erfan Mohammadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Simin Younesi
- School of Health and Biomedical Sciences RMIT University, Melbourne, Vic., Australia.
| | - Ansar Karimian
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Nader Farsad-Akhtar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Fahime Jahanbakhshi
- Department of Gynecology and Obstetrics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Hamidreza Jamilian
- Department of Psychiatry, Arak University of Medical Sciences, Arak, Iran.
| | - Bahman Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
49
|
Huang J, Zhang Y, Xu Y, Xie Q, Wu S, Dong Y, Chen B, Xia Y, Guo L, Li Q, Gu H, Hu W. MiRNA-202-5p promotes Colorectal Carcinogenesis through suppression of PTEN. J Cancer 2021; 12:3154-3163. [PMID: 33976725 PMCID: PMC8100819 DOI: 10.7150/jca.56186] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is still one of the leading causes of cancer-associated death in the modern society. The biological function of miR-202-5p for CRC development remains controversial, largely due to the fact that miR-202-5p can be tumor-suppressive or oncogenic in different contexts. Obtained results indicated that aberrant expression of miR-202-5p was observed in majority of human CRC samples and miR-202-5p was transcriptionally up-regulated by c-Myc. In addition, miR-202-5p functions to promote the activation of PI3K/Akt signaling pathway by directly suppressing PTEN. Silencing or enforced expression of miR-202-5p resulted in CRC cell proliferation inhibition and enhancement, respectively. Importantly, decreased PTEN level and increased phosphorylation of Akt were frequently associated with elevated miR-202-5p expression in colorectal cancer tissues. Increased miR-202-5p expression may serve as a tumor promoter by directly targeting PTEN in colorectal cancer.
Collapse
Affiliation(s)
- Jing Huang
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Yaqin Zhang
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Yuan Xu
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Qi Xie
- Translational Research Institute, Henan Provincial People's Hospital, Molecular Pathology Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China, 450003
| | - Shuang Wu
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Yi Dong
- Translational Research Institute, Henan Provincial People's Hospital, Molecular Pathology Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China, 450003
| | - Bing Chen
- Translational Research Institute, Henan Provincial People's Hospital, Molecular Pathology Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China, 450003
| | - Yang Xia
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Lili Guo
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Qun Li
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Hao Gu
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032
| | - Wanglai Hu
- Department of Immunology, the school of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032.,Translational Research Institute, Henan Provincial People's Hospital, Molecular Pathology Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China, 450003
| |
Collapse
|
|
50
|
Patra S, Pradhan B, Nayak R, Behera C, Panda KC, Das S, Jena M, Bhutia SK. Apoptosis and autophagy modulating dietary phytochemicals in cancer therapeutics: Current evidences and future perspectives. Phytother Res 2021; 35:4194-4214. [DOI: 10.1002/ptr.7082] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022]
Affiliation(s)
- Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science National Institute of Technology Rourkela Rourkela Odisha India
| | - Biswajita Pradhan
- Post Graduate Department of Botany Berhampur University Berhampur Odisha India
| | - Rabindra Nayak
- Post Graduate Department of Botany Berhampur University Berhampur Odisha India
| | - Chhandashree Behera
- Post Graduate Department of Botany Berhampur University Berhampur Odisha India
| | - Krishna Chandra Panda
- Department of Pharmaceutical Chemistry Roland Institute of Pharmaceutical Sciences Berhampur Odisha India
| | - Surajit Das
- Laboratory of Environmental Microbiology and Ecology, Department of Life Science National Institute of Technology Rourkela Rourkela Odisha India
| | - Mrutyunjay Jena
- Post Graduate Department of Botany Berhampur University Berhampur Odisha India
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science National Institute of Technology Rourkela Rourkela Odisha India
| |
Collapse
|