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Xu Y, Zheng Z, Jiang X, Wang X, Xu Q, Lu X, Huang Y, Qin Y, Hou N, Liu Y. Inhibition of Bif-1 confers cardio-protection in myocardial infarction. Am J Physiol Cell Physiol 2025; 328:C1076-C1089. [PMID: 39982446 DOI: 10.1152/ajpcell.00473.2024] [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: 07/09/2024] [Revised: 08/14/2024] [Accepted: 02/06/2025] [Indexed: 02/22/2025]
Abstract
Myocardial infarction (MI) remains a major cause of chronic heart failure. Endoplasmic reticulum (ER) stress is an emerging therapeutic strategy to prevent adverse remodeling of the infarcted heart. However, little is known about how Bax-interacting protein 1 (Bif-1), a member of the endophilin B family, is involved in mediating cardiac ER stress in ischemic heart disease. Here, a combination of a left anterior descending coronary artery ligation mouse model and an adenovirus-based transfection strategy was used to investigate the effect of Bif-1 on cardiac remodeling and function after MI. 4-Phenylbutyric acid (4-PBA) was used to understand the role of ER stress in cardiac remodeling. To discover the molecular mechanism, an RNA sequencing study was performed. We found that Bif-1 expression was highly elevated in the heart infarct border zone post-MI and neonatal rat cardiomyocytes treated with oxygen and glucose deprivation. Adenovirus-based knockdown of Bif-1 protected the heart from MI as demonstrated by attenuated maladaptive remodeling and preserved contractile function. ER stress inhibition by 4-PBA alleviated the adverse effects of Bif-1 overexpression on cardiac structure and function. Furthermore, we explored the underlying mechanism by RNA sequencing and identified Bif-1 as a molecule involved in cardiac lipid metabolism. In conclusion, our study identifies Bif-1 as a negative regulator of cardiac protection in MI. Inhibition of Bif-1 alleviates ER stress, which may restore lipid metabolism homeostasis to preserve cardiac function post-MI. Therefore, Bif-1 is a potential novel therapeutic target for ischemic heart disease.NEW & NOTEWORTHY Our study demonstrated that Bif-1 contributes to adverse cardiac remodeling and dysfunction following MI by promoting ER stress. Pharmacological inhibition of ER stress ameliorates cardiac remodeling and dysfunction. In addition, we identified Bif-1 as a negative regulator of cardiac lipid metabolism post-MI, as shown by elevated expression of Acox1, Pla2g7, Acsbg1, Acsl5, Ch25h, and Bcat1 in the heart. These findings suggest that Bif-1 plays a crucial role in cardiac decline post-MI.
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Affiliation(s)
- Yi Xu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Zhirui Zheng
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xin Jiang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xinqiuyue Wang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Qiuxia Xu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xianneng Lu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Yipu Huang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Yuan Qin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Ning Hou
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Yun Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China
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Thorlacius A, Rulev M, Sundberg O, Sundborger-Lunna A. Peripheral membrane protein endophilin B1 probes, perturbs and permeabilizes lipid bilayers. Commun Biol 2025; 8:182. [PMID: 39910321 PMCID: PMC11799418 DOI: 10.1038/s42003-025-07610-1] [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: 08/26/2024] [Accepted: 01/27/2025] [Indexed: 02/07/2025] Open
Abstract
Bin/Amphiphysin/Rvs167 (BAR) domain containing proteins are peripheral membrane proteins that regulate intracellular membrane curvature. BAR protein endophilin B1 plays a key role in multiple cellular processes critical for oncogenesis, including autophagy and apoptosis. Amphipathic regions in endophilin B1 drive membrane association and tubulation through membrane scaffolding. Our understanding of exactly how BAR proteins like endophilin B1 promote highly diverse intracellular membrane remodeling events in the cell is severely limited due to lack of high-resolution structural information. Here we present the highest resolution cryo-EM structure of a BAR protein to date and the first structures of a BAR protein bound to a lipid bicelle. Using neural networks, we can effectively sort particle species of different stoichiometries, revealing the tremendous flexibility of post-membrane binding, pre-polymer BAR dimer organization and membrane deformation. We also show that endophilin B1 efficiently permeabilizes negatively charged liposomes that contain mitochondria-specific lipid cardiolipin and propose a new model for Bax-mediated cell death.
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Affiliation(s)
- Arni Thorlacius
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Maksim Rulev
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Oscar Sundberg
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
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Rahmati S, Moeinafshar A, Rezaei N. The multifaceted role of extracellular vesicles (EVs) in colorectal cancer: metastasis, immune suppression, therapy resistance, and autophagy crosstalk. J Transl Med 2024; 22:452. [PMID: 38741166 PMCID: PMC11092134 DOI: 10.1186/s12967-024-05267-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
Extracellular vesicles (EVs) are lipid bilayer structures released by all cells and widely distributed in all biological fluids. EVs are implicated in diverse physiopathological processes by orchestrating cell-cell communication. Colorectal cancer (CRC) is one of the most common cancers worldwide, with metastasis being the leading cause of mortality in CRC patients. EVs contribute significantly to the advancement and spread of CRC by transferring their cargo, which includes lipids, proteins, RNAs, and DNAs, to neighboring or distant cells. Besides, they can serve as non-invasive diagnostic and prognostic biomarkers for early detection of CRC or be harnessed as effective carriers for delivering therapeutic agents. Autophagy is an essential cellular process that serves to remove damaged proteins and organelles by lysosomal degradation to maintain cellular homeostasis. Autophagy and EV release are coordinately activated in tumor cells and share common factors and regulatory mechanisms. Although the significance of autophagy and EVs in cancer is well established, the exact mechanism of their interplay in tumor development is obscure. This review focuses on examining the specific functions of EVs in various aspects of CRC, including progression, metastasis, immune regulation, and therapy resistance. Further, we overview emerging discoveries relevant to autophagy and EVs crosstalk in CRC.
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Affiliation(s)
- Soheil Rahmati
- Student Research Committee, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Aysan Moeinafshar
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Yang LQ, Huang AF, Xu WD. Biology of endophilin and it's role in disease. Front Immunol 2023; 14:1297506. [PMID: 38116012 PMCID: PMC10728279 DOI: 10.3389/fimmu.2023.1297506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/22/2023] [Indexed: 12/21/2023] Open
Abstract
Endophilin is an evolutionarily conserved family of protein that involves in a range of intracellular membrane dynamics. This family consists of five isoforms, which are distributed in various tissues. Recent studies have shown that Endophilin regulates diseases pathogenesis, including neurodegenerative diseases, tumors, cardiovascular diseases, and autoimmune diseases. In vivo, it regulates different biological functions such as vesicle endocytosis, mitochondrial morphological changes, apoptosis and autophagosome formation. Functional studies confirmed the role of Endophilin in development and progression of these diseases. In this study, we have comprehensively discussed the complex function of Endophilin and how the family contributes to diseases development. It is hoped that this study will provide new ideas for targeting Endophilin in diseases.
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Affiliation(s)
- Lu-Qi Yang
- Department of Evidence-Based Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - An-Fang Huang
- Department of Rheumatology and Immunology, Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Wang-Dong Xu
- Department of Evidence-Based Medicine, Southwest Medical University, Luzhou, Sichuan, China
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Komarla A, Dufresne S, Towers CG. Recent Advances in the Role of Autophagy in Endocrine-Dependent Tumors. Endocr Rev 2023; 44:629-646. [PMID: 36631217 PMCID: PMC10335171 DOI: 10.1210/endrev/bnad001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 10/31/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Autophagy plays a complex role in several cancer types, including endocrine-dependent cancers, by fueling cellular metabolism and clearing damaged substrates. This conserved recycling process has a dual function across tumor types where it can be tumor suppressive at early stages but tumor promotional in established disease. This review highlights the controversial roles of autophagy in endocrine-dependent tumors regarding cancer initiation, tumorigenesis, metastasis, and treatment response. We summarize clinical trial results thus far and highlight the need for additional mechanistic, preclinical, and clinical studies in endocrine-dependent tumors, particularly in breast cancer and prostate cancer.
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Affiliation(s)
- Anvita Komarla
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
- The Cell and Molecular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Suzanne Dufresne
- The Cell and Molecular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Christina G Towers
- The Cell and Molecular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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6
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Mohammadi K, Salimi M, Angaji SA, Saniotis A, Mahjoobi F. Association study of Bif-1 gene expression with histopathological characteristics and hormone receptors in breast cancer. BMC Womens Health 2022; 22:471. [PMID: 36434659 PMCID: PMC9701003 DOI: 10.1186/s12905-022-02075-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 11/15/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Breast cancer is a heterogeneous disease that has various clinical outcomes. Bax-interacting factor-1 (Bif-1) is a member of the endophilin B family that generates the pro-apoptotic BCL2-Associated X (BAX) protein in response to apoptotic signals. Lack of Bif-1 inhibits the intrinsic pathway of apoptosis and enhancements the risk of tumor genesis. The present study aimed to investigate the relationship between hormone receptors (ER, PR, and HER2) status and different levels of Bif-1 gene expression in breast cancer patients. METHODS Bif-1 gene expression was evaluated in 50 breast cancer tumors and 50 normal breast mammary tissues using the SYBR Green real-time RT-PCR technique. Multivariate and univariate analyses were used to appraise the relationship between the prognostic significance of the Bif-1 gene using SPSS software. In this study, the Bif-1 was selected as a candidate for a molecular biomarker and its expression status in breast cancer patients with hormone receptors (ER, RR, and HER2) compared to patients without these hormone receptors. RESULTS The study showed that the relative expression of the Bif-1 gene in tissues of patients with hormone receptors in breast cancer compared to those without hormone receptors was not statistically significant. The expression levels of the Bif-1 gene in different groups were evaluated for hormone receptor status. No significant relationship was found between the Bif-1 gene expression and hormone receptors (ER, PR, and HER2) (p > 0.05). CONCLUSION Bif-1 gene expression may be a useful prognostic marker in breast cancer.
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Affiliation(s)
- Kazhaleh Mohammadi
- grid.513517.40000 0005 0233 0078Department of Pharmacy, College of Pharmacy, Knowledge University, Erbil, 44001 Iraq
| | - Mahdieh Salimi
- grid.419420.a0000 0000 8676 7464Department of Medical Genetic, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - S. Abdolhamid Angaji
- grid.412265.60000 0004 0406 5813Department of Cell and Molecular Biology Sciences, Kharazmi University, Tehran, Iran
| | - Arthur Saniotis
- Bachelors of Doctor Assistant Department, DDT College of Medicine, Gaborone, Botswana ,grid.1010.00000 0004 1936 7304Biological and Comparative Anatomy Research Unit, School of Biomedicine, The University of Adelaide, Adelaide, Australia
| | - Foroozandeh Mahjoobi
- grid.419420.a0000 0000 8676 7464Department of Medical Genetic, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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7
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Marzoog BA. Autophagy in Cancer Cell Transformation: A Potential Novel Therapeutic Strategy. Curr Cancer Drug Targets 2022; 22:749-756. [PMID: 36062863 DOI: 10.2174/1568009622666220428102741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 01/18/2023]
Abstract
Basal autophagy plays a crucial role in maintaining intracellular homeostasis and prevents the cell from escaping the cell cycle regulation mechanisms and being cancerous. Mitophagy and nucleophagy are essential for cell health. Autophagy plays a pivotal role in cancer cell transformation, where upregulated precancerous autophagy induces apoptosis. Impaired autophagy has been shown to upregulate cancer cell transformation. However, tumor cells upregulate autophagy to escape elimination and survive the unfavorable conditions and resistance to chemotherapy. Cancer cells promote autophagy through modulation of autophagy regulation mechanisms and increase expression of the autophagyrelated genes. Whereas, autophagy regulation mechanisms involved microRNAs, transcription factors, and the internalized signaling pathways such as AMPK, mTOR, III PI3K, and ULK-1. Disrupted regulatory mechanisms are various as the cancer cell polymorphism. Targeting a higher level of autophagy regulation is more effective, such as gene expression, transcription factors, or epigenetic modification that are responsible for the up-regulation of autophagy in cancer cells. Currently, the CRISPR-CAS9 technique is available and can be applied to demonstrate the potential effects of autophagy in cancerous cells.
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Affiliation(s)
- Basheer Abdullah Marzoog
- National Research Mordovia State University, Bolshevitskaya Street, 68, Saransk, Rep. Mordovia 430005, Russian Federation
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Shu Y, Sun X, Ye G, Xu M, Wu Z, Wu C, Li S, Tian J, Han H, Zhang J. DHOK Exerts Anti-Cancer Effect Through Autophagy Inhibition in Colorectal Cancer. Front Cell Dev Biol 2021; 9:760022. [PMID: 34977014 PMCID: PMC8719673 DOI: 10.3389/fcell.2021.760022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/29/2021] [Indexed: 12/24/2022] Open
Abstract
DHOK (14,15β-dihydroxyklaineanone) is a novel diterpene isolated from roots of Eurycoma longifolia Jack, a traditional herb widely applied in Southeast Asia. It is reported that DHOK has cytotoxic effect on cancer cells, but its anti-cancer mechanism has still been not clear. In our study, we first observed that DHOK inhibits cell proliferation of colorectal cancer cells in a time- and dose-dependent manner. Next, we performed transcriptome sequencing to identify the targets of DHOK and found that autophagy-related signaling pathways are involved under DHOK treatment. Indeed, in DHOK-treated cells, the level of autophagosome marker LC3 and the formation of GFP-LC3 puncta were decreased, indicating the reduction of autophagy. Moreover, confocal microscopy results revealed the lysosomal activity and the formation of autolysosomes are also inhibited. Our western blotting results demonstrated the activation of mammalian target of rapamycin (mTOR) signaling pathway by DHOK, which may be attributed to the enhancement of ERK and AKT activity. Functionally, activation of autophagy attenuated DHOK-caused cell death, indicating that autophagy serves as cell survival. In xenograft mouse model, our results also showed that DHOK activates the mTOR signaling pathway, decreases autophagy level and inhibits the tumorigenesis of colon cancer. Taken together, we revealed the molecular mechanism of DHOK against cancer and our results also demonstrate great potential of DHOK in the treatment of colorectal cancer.
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Affiliation(s)
- Yuhan Shu
- College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China
- Department of Oncology, Cancer Center, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xin Sun
- Department of Oncology, Cancer Center, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Guiqin Ye
- Hangzhou Medical College, Hangzhou, China
| | - Mengting Xu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zhipan Wu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Caixia Wu
- Department of Oncology, Cancer Center, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Shouxin Li
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Jingkui Tian
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Haote Han
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- *Correspondence: Jianbin Zhang, ; Haote Han,
| | - Jianbin Zhang
- Department of Oncology, Cancer Center, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
- *Correspondence: Jianbin Zhang, ; Haote Han,
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9
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Shafabakhsh R, Arianfar F, Vosough M, Mirzaei HR, Mahjoubin-Tehran M, Khanbabaei H, Kowsari H, Shojaie L, Azar MEF, Hamblin MR, Mirzaei H. Autophagy and gastrointestinal cancers: the behind the scenes role of long non-coding RNAs in initiation, progression, and treatment resistance. Cancer Gene Ther 2021; 28:1229-1255. [PMID: 33432087 DOI: 10.1038/s41417-020-00272-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/06/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers comprise a heterogeneous group of complex disorders that affect different organs, including esophagus, stomach, gallbladder, liver, biliary tract, pancreas, small intestine, colon, rectum, and anus. Recently, an explosion in nucleic acid-based technologies has led to the discovery of long non-coding RNAs (lncRNAs) that have been found to possess unique regulatory functions. This class of RNAs is >200 nucleotides in length, and is characterized by their lack of protein coding. LncRNAs exert regulatory effects in GI cancer development by affecting different functions such as the proliferation and metastasis of cancer cells, apoptosis, glycolysis and angiogenesis. Over the past few decades, considerable evidence has revealed the important role of autophagy in both GI cancer progression and suppression. In addition, recent studies have confirmed a significant correlation between lncRNAs and the regulation of autophagy. In this review, we summarize how lncRNAs play a behind the scenes role in the pathogenesis of GI cancers through regulation of autophagy.
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Affiliation(s)
- Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Farzaneh Arianfar
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, 1665659911, Iran
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hashem Khanbabaei
- Medical Physics Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hamed Kowsari
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Layla Shojaie
- Research Center for Liver Diseases, Keck School of Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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10
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Yang Y, Zhou L, Xue F, An L, Jin M, Li L. Transmembrane Protein 166 and its Significance. Protein Pept Lett 2021; 28:382-387. [PMID: 33006534 DOI: 10.2174/0929866527666201002150316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/15/2020] [Accepted: 08/11/2020] [Indexed: 12/30/2022]
Abstract
Transmembrane protein 166 (TMEM166) is a lysosomal/endoplasmic reticulum (ER)-associated protein found in different species where it functions as a regulator of programmed cell death through autophagy and apoptosis. It is expressed in a variety of normal tissues and organs, and it is involved in a wide variety of physiological and pathological processes, including cancers, infection, autoimmune diseases, and neurodegenerative diseases. Previous studies indicated that TMEM166 is associated with autophagosomal membrane development. TMEM166 can cause lysosomal membrane permeabilization (LMP) leading to the release of proteolytic enzymes, e.g., cathepsins, that may cause potential mitochondrial membrane damage, which triggers several autophagic and apoptotic events. A low level of TMEM166 expression is also found in tumors, while high level of TMEM166 is found in brain ischemia. In addition, loss of TMEM166 leads to impaired NSC self-renewal and differentiation along with a decrease in autophagy. These findings offer a comprehensive understanding of the pathways involved in the role of TMEM166 in programmed cell death and treatment of various diseases.
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Affiliation(s)
- Yanwei Yang
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lingxue Zhou
- Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Fushan Xue
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lixin An
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mu Jin
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Li Li
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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11
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Frangež Ž, Seyed Jafari SM, Hunger RE, Simon HU. Loss of Concurrent Regulation of the Expression of BIF-1, BAX, and Beclin-1 in Primary and Metastatic Melanoma. BIOCHEMISTRY (MOSCOW) 2021; 85:1227-1234. [PMID: 33202207 DOI: 10.1134/s0006297920100107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Melanoma is one of the most aggressive and drug-resistant cancers. Despite novel promising therapeutic strategies, the prognosis of metastatic melanoma patients remains poor and it is often associated with high relapse rates. Endophilin B1, also known as BIF-1, is a multifunctional protein involved in several biological processes such as autophagy and apoptosis. BIF-1 promotes apoptosis through binding to BAX and its translocation to the mitochondrial outer membrane. On the other hand, BIF-1 can interact with Beclin-1 through UVRAG to promote autophagy. Several reports suggest an ambiguous role of BIF-1 in cancer development and progression. For example, it has been demonstrated that the expression of BIF-1 is reduced in both primary and metastatic melanoma and that the reduction of BIF-1 expression is associated with reduced overall survival of melanoma patients. Here we show that the expression of Beclin-1 and active form of BAX are also reduced in the melanoma patients. However, while we observed strong positive correlations between the expression of BIF-1 and Beclin-1 as well as between BIF-1 and BAX in benign nevi, these correlations were lost in the primary and metastatic melanoma cells. These data indicate disruption in the proximal molecular mechanisms which regulate expression of BIF-1, Beclin-1, and BAX in the primary and metastatic melanoma.
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Affiliation(s)
- Ž Frangež
- Institute of Pharmacology, University of Bern, Bern, 3010, Switzerland
| | - S M Seyed Jafari
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, 3010, Switzerland
| | - R E Hunger
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, 3010, Switzerland
| | - H-U Simon
- Institute of Pharmacology, University of Bern, Bern, 3010, Switzerland. .,Department of Clinical Immunology and Allergology, Sechenov University, Moscow, 119435, Russia
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12
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Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts. Cancers (Basel) 2021; 13:cancers13061258. [PMID: 33809172 PMCID: PMC7998818 DOI: 10.3390/cancers13061258] [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: 02/04/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary We investigated the influence of autophagy-related variants in modulating colorectal cancer (CRC) risk through a meta-analysis of genome-wide association study (GWAS) data from four large European cohorts. We found that genetic variants within the DAPK2 and ATG5 loci were associated with CRC risk. This study also shed some light onto the functional mechanisms behind the observed associations and demonstrated the impact of DAPK2rs11631973 and ATG5rs546456 polymorphisms on the modulation of host immune responses, blood derived-cell counts and serum inflammatory protein levels, which might be involved in promoting cancer development. No effect of the DAPK2 and ATG5 polymorphisms on the autophagy flux was observed. Abstract The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, DAPK2 (p = 2.19 × 10−5) and ATG5 (p = 6.28 × 10−4) were associated with the risk of CRC. Mechanistically, the DAPK2rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses.
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Abstract
Autophagy is an evolutionarily conserved process necessary to maintain cell homeostasis in response to various forms of stress such as nutrient deprivation and hypoxia as well as functioning to remove damaged molecules and organelles. The role of autophagy in cancer varies depending on the stage of cancer. Cancer therapeutics can also simultaneously evoke cancer cell senescence and ploidy increase. Both cancer cell senescence and polyploidization are reversible by depolyploidization giving rise to the progeny. Autophagy activation may be indispensable for cancer cell escape from senescence/polyploidy. As cancer cell polyploidy is proposed to be involved in cancer origin, the role of autophagy in polyploidization/depolyploidization of senescent cancer cells seems to be crucial. Accordingly, this review is an attempt to understand the complicated interrelationships between reversible cell senescence/polyploidy and autophagy.
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14
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Broggi G, Ieni A, Russo D, Varricchio S, Puzzo L, Russo A, Reibaldi M, Longo A, Tuccari G, Staibano S, Caltabiano R. The Macro-Autophagy-Related Protein Beclin-1 Immunohistochemical Expression Correlates With Tumor Cell Type and Clinical Behavior of Uveal Melanoma. Front Oncol 2020; 10:589849. [PMID: 33330070 PMCID: PMC7714947 DOI: 10.3389/fonc.2020.589849] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/20/2020] [Indexed: 01/01/2023] Open
Abstract
Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10-15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.
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Affiliation(s)
- Giuseppe Broggi
- Section of Anatomic Pathology, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy
| | - Antonio Ieni
- Section of Pathology, Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
| | - Daniela Russo
- Pathology Unit, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Silvia Varricchio
- Pathology Unit, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Lidia Puzzo
- Section of Anatomic Pathology, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy
| | - Andrea Russo
- Department of Ophthalmology, University of Catania, Catania, Italy
| | - Michele Reibaldi
- Department of Ophthalmology, University of Catania, Catania, Italy.,Department of Surgical Science, Eye Clinic, University of Torino, Torino, Italy
| | - Antonio Longo
- Department of Ophthalmology, University of Catania, Catania, Italy
| | - Giovanni Tuccari
- Section of Pathology, Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
| | - Stefania Staibano
- Pathology Unit, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
| | - Rosario Caltabiano
- Section of Anatomic Pathology, Department Gian Filippo Ingrassia, University of Catania, Catania, Italy
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15
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Farhan M, Silva M, Li S, Yan F, Fang J, Peng T, Hu J, Tsao M, Little P, Zheng W. The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development. Med Res Rev 2020; 40:2089-2113. [PMID: 32474970 PMCID: PMC7586888 DOI: 10.1002/med.21695] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 04/21/2020] [Accepted: 05/16/2020] [Indexed: 12/17/2022]
Abstract
Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.
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Affiliation(s)
- Mohd Farhan
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Marta Silva
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Shuai Li
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Fengxia Yan
- Department of MedicineJinan UniversityGuangzhouChina
| | - Jiankang Fang
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Tangming Peng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Jim Hu
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Ming‐Sound Tsao
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Peter Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of QueenslandWoolloongabbaQueenslandAustralia
| | - Wenhua Zheng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
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Shi Y, He R, Yang Y, He Y, Zhan L, Wei B. Potential relationship between Sirt3 and autophagy in ovarian cancer. Oncol Lett 2020; 20:162. [PMID: 32934730 PMCID: PMC7471650 DOI: 10.3892/ol.2020.12023] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023] Open
Abstract
Sirtuin 3 (Sirt3) is an important member of the sirtuin protein family. It is a deacetylase that was previously reported to modulate the level of reactive oxygen species (ROS) production and limit the extent of oxidative damage in cellular components. As an important member of the class III type of histone deacetylases, Sirt3 has also been documented to mediate nuclear gene expression, metabolic control, neuroprotection, cell cycle and proliferation. In ovarian cancer (OC), Sirt3 has been reported to regulate cellular metabolism, apoptosis and autophagy. Sirt3 can regulate autophagy through a variety of different molecular signaling pathways, including the p62, 5'AMP-activated protein kinase and mitochondrial ROS-superoxide dismutase pathways. However, autophagy downstream of Sirt3 and its association with OC remains poorly understood. In the present review, the known characteristics of Sirt3 and autophagy were outlined, and their potential functional roles were discussed. Following a comprehensive analysis of the current literature, Sirt3 and autophagy may either serve positive or negative roles in the regulation of OC. Therefore, it is important to identify the appropriate expression level of Sirt3 to control the activation of autophagy in OC cells. This strategy may prove to be a novel therapeutic method to reduce the mortality of patients with OC. Finally, potential research directions into the association between Sirt3 and other signaling pathways were provided.
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Affiliation(s)
- Yuchuan Shi
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Runhua He
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Yu Yang
- Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Yu He
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Lei Zhan
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China.,Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Bing Wei
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
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17
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Frangež Ž, Fernández-Marrero Y, Stojkov D, Seyed Jafari SM, Hunger RE, Djonov V, Riether C, Simon HU. BIF-1 inhibits both mitochondrial and glycolytic ATP production: its downregulation promotes melanoma growth. Oncogene 2020; 39:4944-4955. [PMID: 32493957 DOI: 10.1038/s41388-020-1339-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 05/19/2020] [Accepted: 05/27/2020] [Indexed: 11/09/2022]
Abstract
Endophilin B1, also known as BAX-interacting protein 1 (BIF-1), is part of the endophilin B protein family, and is a multifunctional protein involved in the regulation of apoptosis, autophagy, and mitochondrial morphology. The role of BIF-1 in cancer is controversial since previous reports indicated to both tumor-promoting and tumor-suppressive roles, perhaps depending on the cancer cell type. In the present study, we report that BIF-1 is significantly downregulated in both primary and metastatic melanomas, and that patients with high levels of BIF-1 expression exhibited a better overall survival. Depleting BIF-1 using CRISPR/Cas9 technology in melanoma cells resulted in higher proliferation rates both in vitro and in vivo, a finding that was associated with increased ATP production, metabolic acidification, and mitochondrial respiration. We also observed mitochondrial hyperpolarization, but no increase in the mitochondrial content of BIF-1-knockout melanoma cells. In contrast, such knockout melanoma cells were equally sensitive to anticancer drug- or UV irradiation-induced cell death, and exhibited similar autophagic activities as compared with control cells. Taken together, it appears that downregulation of BIF-1 contributes to tumorigenesis in cutaneous melanoma by upregulating mitochondrial respiration and metabolism, independent of its effect on apoptosis and autophagy.
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Affiliation(s)
- Živa Frangež
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | | | - Darko Stojkov
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - S Morteza Seyed Jafari
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Robert E Hunger
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | | | - Carsten Riether
- Tumor Immunology, Department for Biomedical Research, University of Bern, Bern, Switzerland.,Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland. .,Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia.
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18
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Abstract
Apoptosis is a form of programmed cell death that is essential for tissue homeostasis. De-regulation of the balance between proliferation and apoptosis contributes to tumor initiation. Particularly in the colon where apoptosis is a crucial process in intestinal turnover, inhibition of apoptosis facilitates transformation and tumor progression. The BCL-2 family of proteins are key regulators of apoptosis and have been implicated in colorectal cancer (CRC) initiation, progression and resistance to therapy. In this review we outline the current knowledge on the BCL-2 family-regulated intrinsic apoptosis pathway and mechanisms by which it is de-regulated in CRC. We further review BH3 mimetics as a therapeutic opportunity to target this pathway and evaluate their potential for CRC treatment.
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Affiliation(s)
- Prashanthi Ramesh
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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19
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Humbert M, Morán M, de la Cruz-Ojeda P, Muntané J, Wiedmer T, Apostolova N, McKenna SL, Velasco G, Balduini W, Eckhart L, Janji B, Sampaio-Marques B, Ludovico P, Žerovnik E, Langer R, Perren A, Engedal N, Tschan MP. Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot. BIOLOGY 2020; 9:E59. [PMID: 32245178 PMCID: PMC7150830 DOI: 10.3390/biology9030059] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/18/2020] [Accepted: 03/19/2020] [Indexed: 12/14/2022]
Abstract
Autophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in human tissues, an endeavor that is hampered by the fact that autophagy is characterized by the flux of substrates whereas histology informs only about amounts and localization of substrates and regulators at a single timepoint. Despite this challenging task, considerable progress in establishing markers of autophagy has been made in recent years. The importance of establishing clear-cut autophagy markers that can be used for tissue analysis cannot be underestimated. In this review, we attempt to summarize known techniques to quantify autophagy in human tissue and their drawbacks. Furthermore, we provide some recommendations that should be taken into consideration to improve the reliability and the interpretation of autophagy biomarkers in human tissue samples.
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Grants
- none Bernese Cancer League
- none Stiftung für klinisch-experimentelle Tumorforschung
- none Werner and Hedy Berger-Janser Foundation for Cancer Research
- PI14/01085 and PI17/00093 FIS and FEDER funds from the EU
- CPII16/00023 ISCIII and FSE funds
- RTI2018-096748-B-100 the Spanish Minsitry of Science, Innovation and Universities
- none University Professor Training Fellowship, Ministry of Science, Innovation and University, Government of Spain
- PI18/00442 the State Plan for R & D + I2013-2016 and funded by the Instituto de Salud Carlos III
- none European Regional Development Fund
- C18/BM/12670304/COMBATIC Luxembourg National Research Fund
- NORTE-01-0145-FEDER-000013 Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, by the European Regional Development Fund (FEDER), through the Competitiveness Factors Operational Programme (COMPETE)
- POCI-01-0145-FEDER-028159 and POCI-01-0145-FEDER-030782 FEDER, through the COMPETE
- none National funds, through the Foundation for Science and Technology (FCT
- none ARRS - the Slovenian research agency, programme P1-0140: Proteolysis and its regulation
- KFS-3360-02-2014 the Swiss Cancer Research
- KFS-3409-02-2014 the Swiss Cancer Research
- 31003A_173219 Swiss National Science Foundation
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Affiliation(s)
- Magali Humbert
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - María Morán
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigación Sanitaria Hospital ‘12 de Octubre’ (‘imas12’), 28041 Madrid, Spain
- Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
| | - Patricia de la Cruz-Ojeda
- Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Seville, Spain;
- Department of Surgery, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Jordi Muntané
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Seville, Spain;
- Department of Surgery, School of Medicine, University of Seville, 41009 Seville, Spain
- Spanish Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
| | - Tabea Wiedmer
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - Nadezda Apostolova
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Spanish Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
- Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
| | - Sharon L. McKenna
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Cancer Research at UCC, Western Gateway Building, University College Cork, T12 XF62 Cork, Ireland
| | - Guillermo Velasco
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, and Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Walter Balduini
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Leopold Eckhart
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Bassam Janji
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology—Luxembourg Institute of Health, 1526 Luxembourg City, Luxembourg
| | - Belém Sampaio-Marques
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Paula Ludovico
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Eva Žerovnik
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia
| | - Rupert Langer
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - Aurel Perren
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - Nikolai Engedal
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway
| | - Mario P. Tschan
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
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20
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Interaction between DNA damage response and autophagy in colorectal cancer. Gene 2020; 730:144323. [DOI: 10.1016/j.gene.2019.144323] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 12/21/2019] [Accepted: 12/30/2019] [Indexed: 12/17/2022]
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21
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Khan T, Relitti N, Brindisi M, Magnano S, Zisterer D, Gemma S, Butini S, Campiani G. Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas. Med Res Rev 2019; 40:1002-1060. [PMID: 31742748 DOI: 10.1002/med.21646] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/16/2019] [Accepted: 11/08/2019] [Indexed: 02/06/2023]
Abstract
Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC. Additionally, we provide a viewpoint on the state of the art and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC.
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Affiliation(s)
- Tuhina Khan
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Nicola Relitti
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Margherita Brindisi
- Department of Pharmacy, Department of Excellence 2018-2022, University of Napoli Federico IL, Napoli, Italy
| | - Stefania Magnano
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin, Dublin 2, Ireland
| | - Daniela Zisterer
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin, Dublin 2, Ireland
| | - Sandra Gemma
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Stefania Butini
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Giuseppe Campiani
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
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22
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Kardideh B, Samimi Z, Norooznezhad F, Kiani S, Mansouri K. Autophagy, cancer and angiogenesis: where is the link? Cell Biosci 2019; 9:65. [PMID: 31428311 PMCID: PMC6693242 DOI: 10.1186/s13578-019-0327-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 08/04/2019] [Indexed: 01/12/2023] Open
Abstract
Background Autophagy is a catabolic process for degradation of intracellular components. Damaged proteins and organelles are engulfed in double-membrane vesicles ultimately fused with lysosomes. These vesicles, known as phagophores, develop to form autophagosomes. Encapsulated components are degraded after autophagosomes and lysosomes are fused. Autophagy clears denatured proteins and damaged organelles to produce macromolecules further reused by cells. This process is vital to cell homeostasis under both physiologic and pathologic conditions. Main body While the role of autophagy in cancer is quite controversial, the majority of studies introduce it as an anti-tumorigenesis mechanism. There are evidences confirming this role of autophagy in cancer. Mutations and monoallelic deletions have been demonstrated in autophagy-related genes correlating with cancer promotion. Another pathway through which autophagy suppresses tumorigenesis is cell cycle. On the other hand, under hypoxia and starvation condition, tumors use angiogenesis to provide nutrients. Also, autophagy flux is highlighted in vessel cell biology and vasoactive substances secretion from endothelial cells. The matrix proteoglycans such as Decorin and Perlecan could also interfere with angiogenesis and autophagy signaling pathway in endothelial cells (ECs). It seems that the connection between autophagy and angiogenesis in the tumor microenvironment is very important in determining the fate of cancer cells. Conclusion Matrix glycoproteins can regulate autophagy and angiogenesis linkage in tumor microenvironment. Also, finding details of how autophagy and angiogenesis correlate in cancer will help adopt more effective therapeutic approaches.
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Affiliation(s)
- Bahareh Kardideh
- 1Immunology Department, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.,2Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6714967346 Iran
| | - Zahra Samimi
- 1Immunology Department, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Norooznezhad
- 2Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6714967346 Iran
| | - Sarah Kiani
- 2Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6714967346 Iran
| | - Kamran Mansouri
- 2Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6714967346 Iran.,3Molecular Medicine Department, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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23
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Yun CW, Lee SH. The Roles of Autophagy in Cancer. Int J Mol Sci 2018; 19:ijms19113466. [PMID: 30400561 PMCID: PMC6274804 DOI: 10.3390/ijms19113466] [Citation(s) in RCA: 667] [Impact Index Per Article: 95.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 10/29/2018] [Accepted: 11/02/2018] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an intracellular degradative process that occurs under several stressful conditions, including organelle damage, the presence of abnormal proteins, and nutrient deprivation. The mechanism of autophagy initiates the formation of autophagosomes that capture degraded components and then fuse with lysosomes to recycle these components. The modulation of autophagy plays dual roles in tumor suppression and promotion in many cancers. In addition, autophagy regulates the properties of cancer stem-cells by contributing to the maintenance of stemness, the induction of recurrence, and the development of resistance to anticancer reagents. Although some autophagy modulators, such as rapamycin and chloroquine, are used to regulate autophagy in anticancer therapy, since this process also plays roles in both tumor suppression and promotion, the precise mechanism of autophagy in cancer requires further study. In this review, we will summarize the mechanism of autophagy under stressful conditions and its roles in tumor suppression and promotion in cancer and in cancer stem-cells. Furthermore, we discuss how autophagy is a promising potential therapeutic target in cancer treatment.
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Affiliation(s)
- Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31538, Korea.
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24
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Autophagy in cancer: a complex relationship. Biochem J 2018; 475:1939-1954. [DOI: 10.1042/bcj20170847] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 05/21/2018] [Accepted: 05/22/2018] [Indexed: 12/27/2022]
Abstract
Macroautophagy is the process by which cells package and degrade cytosolic components, and recycle the breakdown products for future use. Since its initial description by Christian de Duve in the 1960s, significant progress has been made in understanding the mechanisms that underlie this vital cellular process and its specificity. Furthermore, macroautophagy is linked to pathologic conditions such as cancer and is being studied as a therapeutic target. In this review, we will explore the connections between autophagy and cancer, which are tumor- and context-dependent and include the tumor microenvironment. We will highlight the importance of tumor compartment-specific autophagy in both cancer aggressiveness and treatment.
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25
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Serfass JM, Takahashi Y, Zhou Z, Kawasawa YI, Liu Y, Tsotakos N, Young MM, Tang Z, Yang L, Atkinson JM, Chroneos ZC, Wang HG. Endophilin B2 facilitates endosome maturation in response to growth factor stimulation, autophagy induction, and influenza A virus infection. J Biol Chem 2017; 292:10097-10111. [PMID: 28455444 PMCID: PMC5473216 DOI: 10.1074/jbc.m117.792747] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 04/27/2017] [Indexed: 12/19/2022] Open
Abstract
Endocytosis, and the subsequent trafficking of endosomes, requires dynamic physical alterations in membrane shape that are mediated in part by endophilin proteins. The endophilin B family of proteins contains an N-terminal Bin/amphiphysin/Rvs (N-BAR) domain that induces membrane curvature to regulate intracellular membrane dynamics. Whereas endophilin B1 (SH3GLB1/Bif-1) is known to be involved in a number of cellular processes, including apoptosis, autophagy, and endocytosis, the cellular function of endophilin B2 (SH3GLB2) is not well understood. In this study, we used genetic approaches that revealed that endophilin B2 is not required for embryonic development in vivo but that endophilin B2 deficiency impairs endosomal trafficking in vitro, as evidenced by suppressed endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry and replication. Mechanistically, although the loss of endophilin B2 did not affect endocytic internalization and lysosomal function, endophilin B2 appeared to regulate the trafficking of endocytic vesicles and autophagosomes to late endosomes or lysosomes. Moreover, we also found that despite having an intracellular localization and tissue distribution similar to endophilin B1, endophilin B2 is dispensable for mitochondrial apoptosis. Taken together, our findings suggest that endophilin B2 positively regulates the endocytic pathway in response to growth factor signaling, autophagy induction, and viral entry.
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Affiliation(s)
| | | | - Zhixiang Zhou
- the Department of Pediatrics
- the College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
| | - Yuka Imamura Kawasawa
- From the Department of Pharmacology
- the Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, and
| | - Ying Liu
- From the Department of Pharmacology
| | | | | | | | | | | | - Zissis C Chroneos
- the Department of Pediatrics
- the Department of Microbiology & Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 and
| | - Hong-Gang Wang
- From the Department of Pharmacology,
- the Department of Pediatrics
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26
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Mokarram P, Albokashy M, Zarghooni M, Moosavi MA, Sepehri Z, Chen QM, Hudecki A, Sargazi A, Alizadeh J, Moghadam AR, Hashemi M, Movassagh H, Klonisch T, Owji AA, Łos MJ, Ghavami S. New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets. Autophagy 2017; 13:781-819. [PMID: 28358273 PMCID: PMC5446063 DOI: 10.1080/15548627.2017.1290751] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.
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Affiliation(s)
- Pooneh Mokarram
- a Colorectal Research Center and Department of Biochemistry , School of Medicine, Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mohammed Albokashy
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Maryam Zarghooni
- c Zabol University of Medical Sciences , Zabol , Iran.,d University of Toronto Alumni , Toronto , ON , Canada
| | - Mohammad Amin Moosavi
- e Department of Molecular Medicine , Institute of Medical Biotechnology, National Institute for Genetic Engineering and Biotechnology , Tehran , Iran
| | - Zahra Sepehri
- c Zabol University of Medical Sciences , Zabol , Iran
| | - Qi Min Chen
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | | | | | - Javad Alizadeh
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Adel Rezaei Moghadam
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Mohammad Hashemi
- g Department of Clinical Biochemistry , School of Medicine, Zahedan University of Medical Sciences , Zahedan , Iran
| | - Hesam Movassagh
- h Department of Immunology , Rady Faculty of Health Sciences, College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Thomas Klonisch
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Ali Akbar Owji
- i Department of Clinical Biochemistry , School of Medicine, Shiraz Medical University , Shiraz , Iran
| | - Marek J Łos
- j Małopolska Centre of Biotechnology , Jagiellonian University , Krakow , Poland ; LinkoCare Life Sciences AB , Sweden
| | - Saeid Ghavami
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada.,k Health Policy Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
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27
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Tang JC, Feng YL, Liang X, Cai XJ. Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer: Trends and Challenges. Chin Med J (Engl) 2017; 129:456-63. [PMID: 26879020 PMCID: PMC4800847 DOI: 10.4103/0366-6999.176069] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective: 5-Fluorouracil (5-FU)-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice. This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system. Data Sources: All articles published in English from 1996 to date those assess the synergistic effect of autophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed. The search terms were “autophagy” and “5-FU” and (“colorectal cancer” or “hepatocellular carcinoma” or “pancreatic adenocarcinoma” or “esophageal cancer” or “gallbladder carcinoma” or “gastric cancer”). Study Selection: Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency of autophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized. The exclusion criteria for the articles were as follows: (1) new materials (e.g., nanomaterial)-induced autophagy; (2) clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers; and (3) immunogenic cell death for anticancer chemotherapy. Results: Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death. Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce. The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials. Conclusion: Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in gastrointestinal cancer.
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Affiliation(s)
| | | | | | - Xiu-Jun Cai
- Department of General Surgery, Zhejiang Province Key Laboratory of Laparosopic Technology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China
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28
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Gil J, Ramsey D, Szmida E, Leszczynski P, Pawlowski P, Bebenek M, Sasiadek MM. The BAX gene as a candidate for negative autophagy-related genes regulator on mRNA levels in colorectal cancer. Med Oncol 2016; 34:16. [PMID: 28035578 PMCID: PMC5199770 DOI: 10.1007/s12032-016-0869-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 12/09/2016] [Indexed: 02/07/2023]
Abstract
Autophagy is a catabolic process, which is involved in the maintenance of intracellular homeostasis by degrading redundant molecules and organelles. Autophagy begins with the formation of a double-membrane phagophore, followed by its enclosure, thus leading to the appearance of an autophagosome which fuses with lysosome. This process is highly conserved, precisely orchestrated and regulated by autophagy-related genes. Recently, autophagy has been widely studied in different types of cancers, including colorectal cancer. As it has been revealed, autophagy plays two opposite roles in tumorigenesis, as a tumor suppressor and a tumor enhancer/activator, and therefore is called a double-edge sword. Recently, interaction between autophagy and apoptosis has been found. Therefore, we aimed to study the mRNA levels of genes engaged in autophagy and apoptosis in colorectal cancer tissues. Colorectal cancer and adjacent healthy tissues were obtained from 73 patients diagnosed with primary colorectal cancer. Real-time PCR analysis employing Universal Probe Library was used to assess the expression of the seven following selected genes: BECN1, UVRAG, ULK1, ATG13, Bif-1, BCL2 and BAX. For all but one of the tested genes, a decrease in expression was observed. An increase in expression was observed for BAX. BAX expression decreases consistently from early to more advanced stages. High expression of BAX was strongly associated with negative UVRAG expression. The high expression of the BAX gene seems to be a negative regulator of autophagy in colorectal cancer cells. The relative downregulation of autophagy-related genes was observed in colorectal cancer samples.
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Affiliation(s)
- Justyna Gil
- Department of Genetics, Wroclaw Medical University, 50-368, Wroclaw, Poland.
| | - David Ramsey
- Department of Operations Research, Wroclaw University of Technology, 50-372, Wroclaw, Poland
| | - Elzbieta Szmida
- Department of Genetics, Wroclaw Medical University, 50-368, Wroclaw, Poland
| | - Przemyslaw Leszczynski
- Department of Biology and Medical Parasitology, Wroclaw Medical University, 50-345, Wroclaw, Poland
| | - Pawel Pawlowski
- Department of Genetics, Wroclaw Medical University, 50-368, Wroclaw, Poland
| | - Marek Bebenek
- First Department of Surgical Oncology, Lower Silesian Oncology Center, 53-413, Wroclaw, Poland
| | - Maria M Sasiadek
- Department of Genetics, Wroclaw Medical University, 50-368, Wroclaw, Poland
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29
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Towers CG, Thorburn A. Therapeutic Targeting of Autophagy. EBioMedicine 2016; 14:15-23. [PMID: 28029600 PMCID: PMC5161418 DOI: 10.1016/j.ebiom.2016.10.034] [Citation(s) in RCA: 211] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 10/20/2016] [Accepted: 10/20/2016] [Indexed: 01/19/2023] Open
Abstract
Autophagy is a catabolic process that facilitates nutrient recycling via degradation of damaged organelles and proteins through lysosomal mediated degradation. Alterations in this complex, and tightly regulated process, lead to disease. Autophagy is widely accepted as cytoprotective against neurodegenerative diseases and a variety of clinical interventions are moving forward to increase autophagy as a therapeutic intervention. Autophagy has both positive and negative roles in cancer and this has led to controversy over whether or how autophagy manipulation should be attempted in cancer therapy. Nevertheless, cancer is the disease where most current activity in trying to manipulate autophagy for therapy is taking place and dozens of clinical trials are using autophagy inhibition with Chloroquine or Hydroxychloroquine in combination with other drugs for the treatment of multiple neoplasms. Here, we review recent literature implicating autophagy in neurodegenerative diseases and cancer and highlight some of the opportunities, controversies and potential pitfalls of therapeutically targeting autophagy.
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Affiliation(s)
- Christina G Towers
- Department of Pharmacology, University of Colorado School of Medicine, 12801 E. 17th Ave, Aurora, CO 80045, USA
| | - Andrew Thorburn
- Department of Pharmacology, University of Colorado School of Medicine, 12801 E. 17th Ave, Aurora, CO 80045, USA.
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30
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Xu L, Wang Z, He SY, Zhang SF, Luo HJ, Zhou K, Li XF, Qiu SP, Cao KY. Bax-interacting factor-1 inhibits cell proliferation and promotes apoptosis in prostate cancer cells. Oncol Rep 2016; 36:3513-3521. [PMID: 27748942 DOI: 10.3892/or.2016.5172] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 08/16/2016] [Indexed: 11/05/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common malignant tumors and the second leading cause of cancer-related death among males. Bax-interacting factor-1 (Bif-1) is a member of Endophilin family, which binds to and activates the BAX protein in response to the apoptosis signaling pathway. Loss of Bif-1 may suppress the intrinsic pathway of apoptosis and promote tumorigenesis, but there is also converse evidence that Bif-1 could in part be responsible for the tumorigenesis and the role of Bif-1 in PCa development is not clear. In the present study, we aimed to understand the relationships between Bif-1 expression and PCa development. The mRNA and protein expression levels of Bif-1 in PCa cell lines, benign prostatic hyperplasia (BPH) (n=100) and PCa tissues (n=100, including low Gleason-scored PCa n=43 and high Gleason-scored PCa n=57) were detected and the effects of Bif-1 overexpression on the apoptosis, proliferation and migration in LNCaP cells were explored. Bif-1 mRNA levels of PCa cell lines were analyzed by real-time PCR and the protein levels were detected by western blotting. Bif-1 expression in BPH and PCa samples was detected by immunohistochemistry. To build Bif-1 overexpression PCa cells, Bif-1 gene was transfected into LNCaP cells by pcDNA3.1(+)‑Bif-1 vector. Cell apoptosis was detected by flow cytometric analysis, cell proliferation measured by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assay and cell migration was analyzed by wound‑healing assay. The results proved that Bif-1 is downregulated in both PCa cell lines (P<0.01) and clinical samples (P<0.05), and Bif-1 expression is suppressed with the cancer progression (BPH vs. PCa P<0.01, and low Gleason-scored PCa vs. high Gleason-scored PCa P<0.05). Overexpression of Bif-1 could significantly inhibit cell proliferation (P<0.05) and enhancing PCa cell apoptosis (P<0.05), but it did not affect the migration ability (P>0.05). Our findings give strong evidence that Bif-1 is involved in PCa tumorigenesis and acts as a suppressor in PCa progression, and may have significance in understanding the process of PCa development.
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Affiliation(s)
- Lin Xu
- Research Center for Clinical Laboratory Standard, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Zhu Wang
- Research Center for Clinical Laboratory Standard, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Shan-Yang He
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510700, P.R. China
| | - Su-Fen Zhang
- Research Center for Clinical Laboratory Standard, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Hong-Jiao Luo
- Research Center for Clinical Laboratory Standard, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Kai Zhou
- Research Center for Clinical Laboratory Standard, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Xiao-Fei Li
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Shao-Peng Qiu
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Kai-Yuan Cao
- Research Center for Clinical Laboratory Standard, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China
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31
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Bif-1 promotes tumor cell migration and metastasis via Cdc42 expression and activity. Clin Exp Metastasis 2016; 34:11-23. [PMID: 27730394 DOI: 10.1007/s10585-016-9825-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 09/30/2016] [Indexed: 12/13/2022]
Abstract
Tumor metastasis is the process by which tumor cells disseminate from tumors and enter nearby and distant microenvironments for new colonization. Bif-1 (BAX-interacting factor 1), which has a BAR domain and an SH3 domain, has been reported to be involved in cell growth, apoptosis and autophagy. However, the influence of Bif-1 on metastasis has been less studied. To understand the role of Bif-1 in metastasis, we studied the expression levels of Bif-1 in human HCC specimens using immunohistochemistry, a tissue microarray and quantitative PCR. The function of Bif-1 was assessed in migration and translocation assays and the pulmonary metastatic animal model. The relationship between Bif-1 and the Rho family was determined using immunoblot analyses and chromatin immunoprecipitation. The results showed that the expression of Bif-1 was higher in hepatocellular carcinoma (HCC) than matched adjacent non-tumor liver tissues. Increased Bif-1 expression was associated with tumor size and the intercellular spread and metastasis of HCC. Analysis of the relationship between Bif-1 expression and patients' clinical characteristics revealed that patients with higher levels of Bif-1 had shorter disease-free and overall survival rates. Knockdown of Bif-1 with RNAi suppressed the migration of HCC cells and pulmonary metastasis and decreased the expression of Cdc42, a member of the Rho family. Bif-1 localized to the cytosol and nucleus and interacted with the promoter transcription region of Cdc42, which may regulate Cdc42 expression. Our results demonstrate a novel role of Bif-1 in HCC, in which Bif-1 promotes cell metastasis by regulating Cdc42 expression and activity.
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32
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Burada F, Nicoli ER, Ciurea ME, Uscatu DC, Ioana M, Gheonea DI. Autophagy in colorectal cancer: An important switch from physiology to pathology. World J Gastrointest Oncol 2015; 7:271-284. [PMID: 26600927 PMCID: PMC4644850 DOI: 10.4251/wjgo.v7.i11.271] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 06/20/2015] [Accepted: 09/30/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC.
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Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, Codogno P, Debnath J, Gewirtz DA, Karantza V, Kimmelman A, Kumar S, Levine B, Maiuri MC, Martin SJ, Penninger J, Piacentini M, Rubinsztein DC, Simon HU, Simonsen A, Thorburn AM, Velasco G, Ryan KM, Kroemer G. Autophagy in malignant transformation and cancer progression. EMBO J 2015; 34:856-80. [PMID: 25712477 PMCID: PMC4388596 DOI: 10.15252/embj.201490784] [Citation(s) in RCA: 940] [Impact Index Per Article: 94.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 01/14/2015] [Accepted: 01/16/2015] [Indexed: 12/15/2022] Open
Abstract
Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.
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Affiliation(s)
- Lorenzo Galluzzi
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Federico Pietrocola
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France
| | - José Manuel Bravo-San Pedro
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France
| | - Ravi K Amaravadi
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Francesco Cecconi
- Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark IRCCS Fondazione Santa Lucia and Department of Biology University of Rome Tor Vergata, Rome, Italy
| | - Patrice Codogno
- Université Paris Descartes Sorbonne Paris Cité, Paris, France Institut Necker Enfants-Malades (INEM), Paris, France INSERM U1151, Paris, France CNRS UMR8253, Paris, France
| | - Jayanta Debnath
- Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - David A Gewirtz
- Department of Pharmacology, Toxicology and Medicine, Virginia Commonwealth University, Richmond Virginia, VA, USA
| | | | - Alec Kimmelman
- Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Beth Levine
- Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Maria Chiara Maiuri
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France
| | - Seamus J Martin
- Department of Genetics, Trinity College, The Smurfit Institute, Dublin, Ireland
| | - Josef Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy National Institute for Infectious Diseases IRCCS 'Lazzaro Spallanzani', Rome, Italy
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Anne Simonsen
- Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Andrew M Thorburn
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Guillermo Velasco
- Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University of Madrid, Madrid, Spain Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain
| | - Kevin M Ryan
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Guido Kroemer
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM U1138, Paris, France Université Paris Descartes Sorbonne Paris Cité, Paris, France Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
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Panda PK, Mukhopadhyay S, Das DN, Sinha N, Naik PP, Bhutia SK. Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics. Semin Cell Dev Biol 2015; 39:43-55. [PMID: 25724561 DOI: 10.1016/j.semcdb.2015.02.013] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 02/12/2015] [Accepted: 02/19/2015] [Indexed: 12/15/2022]
Abstract
Autophagy in cancer is an intensely debated concept in the field of translational research. The dual nature of autophagy implies that it can potentially modulate the pro-survival and pro-death mechanisms in tumor initiation and progression. There is a prospective molecular relationship between defective autophagy and tumorigenesis that involves the accumulation of damaged mitochondria and protein aggregates, which leads to the production of reactive oxygen species (ROS) and ultimately causes DNA damage that can lead to genomic instability. Moreover, autophagy regulates necrosis and is followed by inflammation, which limits tumor metastasis. On the other hand, autophagy provides a survival advantage to detached, dormant metastatic cells through nutrient fueling by tumor-associated stromal cells. Manipulating autophagy for induction of cell death, inhibition of protective autophagy at tissue-and context-dependent for apoptosis modulation has therapeutic implications. This review presents a comprehensive overview of the present state of knowledge regarding autophagy as a new approach to treat cancer.
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Affiliation(s)
- Prashanta Kumar Panda
- Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Subhadip Mukhopadhyay
- Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Durgesh Nandini Das
- Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Niharika Sinha
- Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Prajna Paramita Naik
- Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Sujit K Bhutia
- Department of Life Science, National Institute of Technology Rourkela, Odisha, India.
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Bhutia SK, Mukhopadhyay S, Sinha N, Das DN, Panda PK, Patra SK, Maiti TK, Mandal M, Dent P, Wang XY, Das SK, Sarkar D, Fisher PB. Autophagy: cancer's friend or foe? Adv Cancer Res 2013; 118:61-95. [PMID: 23768510 DOI: 10.1016/b978-0-12-407173-5.00003-0] [Citation(s) in RCA: 166] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The functional relevance of autophagy in tumor formation and progression remains controversial. Autophagy can promote tumor suppression during cancer initiation and protect tumors during progression. Autophagy-associated cell death may act as a tumor suppressor, with several autophagy-related genes deleted in cancers. Loss of autophagy induces genomic instability and necrosis with inflammation in mouse tumor models. Conversely, autophagy enhances survival of tumor cells subjected to metabolic stress and may promote metastasis by enhancing tumor cell survival under environmental stress. Unraveling the complex molecular regulation and multiple diverse roles of autophagy is pivotal in guiding development of rational and novel cancer therapies.
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Affiliation(s)
- Sujit K Bhutia
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India.
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Lorin S, Hamaï A, Mehrpour M, Codogno P. Autophagy regulation and its role in cancer. Semin Cancer Biol 2013; 23:361-79. [DOI: 10.1016/j.semcancer.2013.06.007] [Citation(s) in RCA: 184] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 06/12/2013] [Accepted: 06/18/2013] [Indexed: 12/11/2022]
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Lu H, Li G, Liu L, Feng L, Wang X, Jin H. Regulation and function of mitophagy in development and cancer. Autophagy 2013; 9:1720-36. [PMID: 24091872 DOI: 10.4161/auto.26550] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Beyond its role in recycling intracellular components nonselectively to sustain survival in response to metabolic stresses, autophagy can also selectively degrade specific cargoes such as damaged or dysfunctional organelles to maintain cellular homeostasis. Mitochondria, known as the power plant of cells, are the critical and dynamic organelles playing a fundamental role in cellular metabolism. Mitophagy, the selective autophagic elimination of mitochondria, has been identified both in yeast and in mammalian cells. Moreover, defects in mitophagy may contribute to a variety of human disorders such as neurodegeneration and myopathies. However, the role of mitophagy in development and cancer remains largely unclear. In this review, we summarize our current knowledge of the regulation and function of mitophagy in development and cancer.
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Affiliation(s)
- Haiqi Lu
- Laboratory of Cancer Biology; Institute of Clinical Science; Sir Run Run Shaw Hospital; School of Medicine; Zhejiang University; Hangzhou, Zhejiang China; Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine; Zhejiang University; Hangzhou; Zhejiang China
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Ko YH, Cho YS, Won HS, An HJ, Sun DS, Hong SU, Park JH, Lee MA. Stage-stratified analysis of prognostic significance of Bax-interacting factor-1 expression in resected colorectal cancer. BIOMED RESEARCH INTERNATIONAL 2013; 2013:329839. [PMID: 24175288 PMCID: PMC3794616 DOI: 10.1155/2013/329839] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 08/27/2013] [Accepted: 08/27/2013] [Indexed: 01/03/2023]
Abstract
BACKGROUND/AIM Bax-interacting factor-1 (Bif-1) plays a crucial role in apoptosis and autophagy. The aim of this study was to evaluate Bif-1 protein expression and its prognostic significance in colorectal cancer (CRC). METHODS We analyzed Bif-1 protein expression in 251 resected specimens from patients with CRC by immunohistochemistry using tissue microarray. RESULTS Low Bif-1 expression was observed in 131 patients (52.2%) and high Bif-1 expression in 120 patients (47.8%). No significant differences were observed in clinicopathological parameters between patients with high and low Bif-1 expression. Kaplan-Meier survival analysis showed no difference in survival between patients with high and low Bif-1 expression. Stratified analysis of Bif-1 according to TNM stage demonstrated that low Bif-1 expression was significantly associated with a poor outcome in patients with stages I and II (P = 0.034). Stratified multivariate analysis demonstrated that low Bif-1 expression was an independent indicator of poor prognosis (hazard ratio, 0.459; 95% confidence interval, 0.285-0.739; P = 0.001). CONCLUSION Patients with low levels of Bif-1 expression have shortened survival rates in CRC of stages I and II. This suggests that Bif-1 protein expression may be a useful prognostic marker in early-stage CRC.
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Affiliation(s)
- Yoon Ho Ko
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Young-Seok Cho
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Hye Sung Won
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Ho Jung An
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Der Sheng Sun
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Soon Uk Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Jin Hee Park
- Department of Biomedical Science, The Catholic University of Korea College of Medicine, Seoul 137-701, Republic of Korea
| | - Myung Ah Lee
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul 137-701, Republic of Korea
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Adiseshaiah PP, Clogston JD, McLeland CB, Rodriguez J, Potter TM, Neun BW, Skoczen SL, Shanmugavelandy SS, Kester M, Stern ST, McNeil SE. Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models. Cancer Lett 2013; 337:254-65. [PMID: 23664889 PMCID: PMC3722309 DOI: 10.1016/j.canlet.2013.04.034] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Revised: 03/14/2013] [Accepted: 04/29/2013] [Indexed: 11/24/2022]
Abstract
Autophagy, a catabolic survival pathway, is gaining attention as a potential target in cancer. In human liver and colon cancer cells, treatment with an autophagy inducer, nanoliposomal C6-ceramide, in combination with the autophagy maturation inhibitor, vinblastine, synergistically enhanced apoptotic cell death. Combination treatment resulted in a marked increase in autophagic vacuole accumulation and decreased autophagy maturation, without diminution of the autophagy flux protein P62. In a colon cancer xenograft model, a single intravenous injection of the drug combination significantly decreased tumor growth in comparison to the individual treatments. Most importantly, the combination treatment did not result in increased toxicity as assessed by body weight loss. The mechanism of combination treatment-induced cell death both in vitro and in vivo appeared to be apoptosis. Supportive of autophagy flux blockade as the underlying synergy mechanism, treatment with other autophagy maturation inhibitors, but not autophagy initiation inhibitors, were similarly synergistic with C6-ceramide. Additionally, knockout of the autophagy protein Beclin-1 suppressed combination treatment-induced apoptosis in vitro. In conclusion, in vitro and in vivo data support a synergistic antitumor activity of the nanoliposomal C6-ceramide and vinblastine combination, potentially mediated by an autophagy mechanism.
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Affiliation(s)
- Pavan P. Adiseshaiah
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | - Jeffrey D. Clogston
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | - Christopher B. McLeland
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | - Jamie Rodriguez
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | - Timothy M. Potter
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | - Barry W. Neun
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | - Sarah L. Skoczen
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | | | - Mark Kester
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Stephan T. Stern
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
| | - Scott E. McNeil
- Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702
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Ko YH, Cho YS, Won HS, Jeon EK, An HJ, Hong SU, Park JH, Lee MA. Prognostic significance of autophagy-related protein expression in resected pancreatic ductal adenocarcinoma. Pancreas 2013; 42:829-835. [PMID: 23429496 DOI: 10.1097/mpa.0b013e318279d0dc] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Autophagy is a critical intracellular pathway for the removal of aggregated proteins and damaged organelles. The aim of this study was to explore the contribution of autophagy-related proteins to clinical outcomes of patients with resected pancreatic ductal adenocarcinoma (PDAC). METHODS The expression of 5 autophagy-related proteins in the PDAC tissues of 73 patients was evaluated by immunohistochemistry using a tissue array method. In addition, clinicopathological characteristics and survival were compared with the expression of autophagy-related proteins. RESULTS Of the 73 patients, autophagy-related protein expression frequencies were 49.3% (36/73) for Atg5, 63.9% (46/72) for Ambra1, 47.9% (35/73) for beclin-1, 83.3% (60/72) for LC3B, and 69.9% (51/73) for Bif-1. The correlation between the expressions of autophagy-related proteins was significant for all protein pairs. Advanced T stage was marginally associated with a higher number of protein changes (P = 0.059). Multivariate analysis revealed that beclin-1 overexpression and increases in the alteration of autophagy-related proteins were independently associated with poor prognosis (hazard ratio of 5.365, P = 0.001 and hazard ratio of 5.270, P = 0.022, respectively). CONCLUSIONS The acquisition of autophagy-related proteins is associated with poor clinical outcome in PDAC. The detection and inhibition of autophagy offers a potential therapeutic target for PDAC.
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Affiliation(s)
- Yoon Ho Ko
- Division of Oncology, Department of Internal Medicine, Uijeongbu St Mary's Hospital, Catholic University, Uijeongbu-si, South Korea
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Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy. Blood 2013; 121:1622-32. [PMID: 23287860 DOI: 10.1182/blood-2012-10-459826] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Malignant transformation by oncogenes requires additional genetic/epigenetic changes to overcome enhanced susceptibility to apoptosis. In the present study, we report that Bif-1 (Sh3glb1), a gene encoding a membrane curvature–driving endophilin protein, is a haploinsufficient tumor suppressor that plays a key role in the prevention of chromosomal instability and suppresses the acquisition of apoptosis resistance during Myc-driven lymphomagenesis. Although a large portion of Bif-1–deficient mice harboring an Eμ-Myc transgene displayed embryonic lethality, allelic loss of Bif-1 dramatically accelerated the onset of Myc-induced lymphoma. At the premalignant stage, hemizygous deletion of Bif-1 resulted in an increase in mitochondrial mass, accumulation of DNA damage, and up-regulation of the antiapoptotic protein Mcl-1. Consistently, allelic loss of Bif-1 suppressed the activation of caspase-3 in Myc-induced lymphoma cells. Moreover, we found that Bif-1 is indispensable for the autophagy-dependent clearance of damaged mitochondria (mitophagy), because loss of Bif-1 resulted in the accumulation of endoplasmic reticulum–associated immature autophagosomes and suppressed the maturation of autophagosomes. The results of the present study indicate that Bif-1 haploinsufficiency attenuates mitophagy and results in the promotion of chromosomal instability, which enables tumor cells to efficiently bypass the oncogenic/metabolic pressures for apoptosis. .
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Chang Y, Li Y, Hu J, Guo J, Xu D, Xie H, Lv X, Shi T, Chen Y. Adenovirus vector-mediated expression of TMEM166 inhibits human cancer cell growth by autophagy and apoptosis in vitro and in vivo. Cancer Lett 2013; 328:126-34. [DOI: 10.1016/j.canlet.2012.08.032] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 08/24/2012] [Accepted: 08/24/2012] [Indexed: 01/08/2023]
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Műzes G, Sipos F. Anti-tumor immunity, autophagy and chemotherapy. World J Gastroenterol 2012; 18:6537-6540. [PMID: 23236226 PMCID: PMC3516201 DOI: 10.3748/wjg.v18.i45.6537] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Revised: 10/25/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
Autophagy or self-digestion of cells is activated upon various stressful stimuli and has been found to be a survival and drug resistance pathway in cancer. However, genetic studies support that autophagy can act as a tumor suppressor. Furthermore, defective autophagy is implicated in tumorigenesis, as well. The precise impact of autophagy on malignant transformation has not yet been clarified, but recent data suggest that this complex process is mainly directed by cell types, phases, genetic background and microenvironment. Relation of autophagy to anticancer immune responses may indicate a novel aspect in cancer chemotherapy.
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Sengupta S, Tu SW, Wedin K, Earnest S, Stippec S, Luby-Phelps K, Cobb MH. Interactions with WNK (with no lysine) family members regulate oxidative stress response 1 and ion co-transporter activity. J Biol Chem 2012; 287:37868-79. [PMID: 22989884 DOI: 10.1074/jbc.m112.398750] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Two of the four WNK (with no lysine (K)) protein kinases are associated with a heritable form of ion imbalance culminating in hypertension. WNK1 affects ion transport in part through activation of the closely related Ste20 family protein kinases oxidative stress-responsive 1 (OSR1) and STE20/SPS1-related proline-, alanine-rich kinase (SPAK). Once activated by WNK1, OSR1 and SPAK phosphorylate and stimulate the sodium, potassium, two chloride co-transporters, NKCC1 and NKCC2, and also affect other related ion co-transporters. We find that WNK1 and OSR1 co-localize on cytoplasmic puncta in HeLa and other cell types. We show that the C-terminal region of WNK1 including a coiled coil is sufficient to localize the fragment in a manner similar to the full-length protein, but some other fragments lacking this region are mislocalized. Photobleaching experiments indicate that both hypertonic and hypotonic conditions reduce the mobility of GFP-WNK1 in cells. The four WNK family members can phosphorylate the activation loop of OSR1 to increase its activity with similar kinetic constants. C-terminal fragments of WNK1 that contain three RFXV interaction motifs can bind OSR1, block activation of OSR1 by sorbitol, and prevent the OSR1-induced enhancement of ion co-transporter activity in cells, further supporting the conclusion that association with WNK1 is required for OSR1 activation and function at least in some contexts. C-terminal WNK1 fragments can be phosphorylated by OSR1, suggesting that OSR1 catalyzes feedback phosphorylation of WNK1.
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Affiliation(s)
- Samarpita Sengupta
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA
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Runkle KB, Meyerkord CL, Desai NV, Takahashi Y, Wang HG. Bif-1 suppresses breast cancer cell migration by promoting EGFR endocytic degradation. Cancer Biol Ther 2012; 13:956-66. [PMID: 22785202 DOI: 10.4161/cbt.20951] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Dysregulation of EGFR expression and signaling is well documented to contribute to disease progression and metastasis in many types of cancer including breast cancer. EGF-stimulated EGFR activation leads to receptor internalization and endocytic degradation to control EGFR-mediated signaling. This process is frequently deregulated in cancer cells, leading to increased EGFR expression and mitogenic signaling. Here, we demonstrate that Bif-1, a tumor suppressor, plays a role in EGFR endocytic degradation and chemotactic migration in MDA-MB-231 breast cancer cells. Our data reveal that suppression of Bif-1 expression delays EGFR degradation and sustains Erk1/2 activation in response to EGF stimulation. Mechanistically, loss of Bif-1 sequesters internalized EGF in Rab5-positive endosomes and delays EGFR trafficking to lysosomes. Recruitment of Rab7 to EGF-positive vesicles and the activation of Rab7 are impaired in Bif-1 knockdown cells. Additionally, intracellular pH and the localization of acidic vesicles are altered by suppression of Bif-1. Furthermore, inhibition of Bif-1 increases chemotactic cell migration in response to EGF or serum, which correlates with prolonged cytoskeletal reorganization. Importantly, the effect of Bif-1 on EGF-induced cell migration is abolished by gefitinib, an EGFR-specific inhibitor. Taken together, these data suggest a novel function for Bif-1 as a suppressor of breast cancer cell migration by promoting EGFR degradation through the regulation of endosome maturation.
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Affiliation(s)
- Kristin B Runkle
- Department of Pharmacology and Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA, USA
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Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde? Cancer Lett 2012; 323:115-27. [PMID: 22542808 DOI: 10.1016/j.canlet.2012.02.017] [Citation(s) in RCA: 109] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 02/06/2012] [Accepted: 02/16/2012] [Indexed: 12/13/2022]
Abstract
Autophagy is an evolutionarily conserved mechanism for intracellular substance degradation, responsible for the recycling of metabolic substances and the maintenance of intracellular stability. It has early been demonstrated to play a significant role in tumorigenesis, but whether it acts as a promoter or a suppressor during tumorigenesis seems to be context-specific. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. On the contrary, other reports highlight a tumor-killing role of autophagy during cancer treatment. Herein, this review aims to revisit the key features of autophagy, summarize the seemingly contradictory roles of autophagy during both tumorigenesis and cancer chemotherapy, and evaluate the feasibility of altering the level of cellular autophagy as part of cancer adjuvant treatment.
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Autophagy in the intestinal epithelium is not involved in the pathogenesis of intestinal tumors. Biochem Biophys Res Commun 2012; 421:768-72. [PMID: 22546555 DOI: 10.1016/j.bbrc.2012.04.081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Accepted: 04/15/2012] [Indexed: 11/21/2022]
Abstract
Autophagy has been demonstrated to be associated with the pathogenesis of cancer, but no consensus has been reached about its precise role. Therefore, we investigated whether autophagy in the intestinal epithelium is involved in the pathogenesis of intestinal tumors. To evaluate the relationship between autophagy and intestinal tumors, GFP-LC3-APC(min/+) mice were generated by mating GFP-LC3 transgenic mice with APC(min/+) mice. Autophagy was weakly induced in the intestinal polyp regions of the mice in comparison to their non-polyp regions. Under starved conditions, autophagy was not induced in the polyp regions, whereas it was observed in the non-polyp regions. Then, to examine whether a lack of autophagy in the intestinal epithelium enhances the induction of intestinal tumor, Atg7flox/flox:vil-cre-APC(min/+) mice, in which Atg7 had been conditionally deleted in the intestinal epithelium, were generated by mating Atg7flox/flox:vil-cre mice with APC(min/+) mice. However, there was no significant difference in the number of intestinal polyps between the Atg7flox/flox:vil-cre-APC(min/+) and the corresponding control Atg7flox/flox-APC(min/+) mice. These results indicate that autophagy in the intestinal epithelium is not involved in the pathogenesis of intestinal tumors, and future research should focus on regulating autophagy as a form of cancer therapy.
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Li Y, Zhang J, Liu T, Chen Y, Zeng X, Chen X, He W. Molecular machinery of autophagy and its implication in cancer. Am J Med Sci 2012; 343:155-161. [PMID: 21709535 DOI: 10.1097/maj.0b013e31821f978d] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Autophagy is an intracellular lysosome-dependent catabolic process that is indispensable for maintaining cellular homeostasis through the turnover and elimination of defective or redundant proteins and damaged or aged organelles. Recent studies suggest that autophagy may be closely associated with tumorigenesis and the response of tumor cells to chemotherapeutic drugs. This article reviews recent advances in understanding the molecular mechanisms underlying the regulation of autophagy and the role of autophagy in oncogenesis and anticancer therapy. It is paradoxical that autophagy acts as a mechanism for tumor suppression and contributes to the survival of tumors. In addition, whether autophagy in response to chemotherapies results in cell death or instead protects cancer cells from death is complicated, depending on the nature of the cancer and the drug.
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Affiliation(s)
- Yumin Li
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China; Gansu Provincial Key Laboratory of Digestive System Tumors, Lanzhou, Gansu Province, China.
| | - Junqiang Zhang
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China; Gansu Provincial Key Laboratory of Digestive System Tumors, Lanzhou, Gansu Province, China
| | - Tao Liu
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China; Gansu Provincial Key Laboratory of Digestive System Tumors, Lanzhou, Gansu Province, China
| | - Yingtai Chen
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China; Gansu Provincial Key Laboratory of Digestive System Tumors, Lanzhou, Gansu Province, China
| | - Xiangting Zeng
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China; Gansu Provincial Key Laboratory of Digestive System Tumors, Lanzhou, Gansu Province, China
| | - Xiaohui Chen
- Department of Endocrinology, Gansu Provincial People's Hospital, Lanzhou, Gansu Province, China
| | - Wenting He
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
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Kung CP, Budina A, Balaburski G, Bergenstock MK, Murphy M. Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryot Gene Expr 2012; 21:71-100. [PMID: 21967333 DOI: 10.1615/critreveukargeneexpr.v21.i1.50] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autophagy is a stress-induced cell survival program whereby cells under metabolic, proteotoxic, or other stress remove dysfunctional organelles and/or misfolded/polyubiquitylated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. The end result is the release of free amino acids and metabolites for use in cell survival. For tumor cells, autophagy is a double-edged sword: autophagy genes are frequently mono-allelically deleted, silenced, or mutated in human tumors, resulting in an environment of increased oxidative stress that is conducive to DNA damage, genomic instability, and tumor progression. As such, autophagy is tumor suppressive. In contrast, it is important to note that although tumor cells have reduced levels of autophagy, they do not eliminate this pathway completely. Furthermore, the exposure of tumor cells to an environment of increased metabolic and other stresses renders them reliant on basal autophagy for survival. Therefore, autophagy inhibition is an active avenue for the identification of novel anti-cancer therapies. Not surprisingly, the field of autophagy and cancer has experienced an explosion of research in the past 10 years. This review covers the basic mechanisms of autophagy, discusses its role in tumor suppression and cancer therapy, and posits emerging questions for the future.
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Affiliation(s)
- Che-Pei Kung
- Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
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Fan R, Miao Y, Shan X, Qian H, Song C, Wu G, Chen Y, Zha W. Bif-1 is overexpressed in hepatocellular carcinoma and correlates with shortened patient survival. Oncol Lett 2012; 3:851-854. [PMID: 22741005 DOI: 10.3892/ol.2012.562] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2011] [Accepted: 12/21/2011] [Indexed: 11/06/2022] Open
Abstract
Bax-interacting factor-1 (Bif-1) interacts with Beclin1 [the mammalian ortholog of yeast autophagy-related gene 6 (Atg6)] and affects the formation of autophagosomes during autophagy. The aim of this study was to explore Bif-1 expression and its prognostic significance in comparison with various clinicopathological predictors of survival. Bif-1 protein expression was determined by immunohistochemistry in 206 hepatocellular carcinomas. Cytoplasmic immunoreactivity was scored semi-quantitatively. The results were analyzed in correlation with various clinicopathological characteristics, including patient survival. The Chi-square test and Kaplan-Meier survival analysis were applied. The expression of Bif-1 was significantly higher in the hepatocellular cancers than in the adjacent matched non-tumor tissues (51.5 vs. 33.0%, P<0.01). Increased expression of Bif-1 in hepatocellular carcinomas was significantly correlated with a low grade of differentiation and a shortened overall survival (P<0.05). No significant differences were found between the expression of Bif-1 and age, gender, tumor size, damage of capsule, expression of hepatitis B surface antigen (HBs-Ag) and portal venous invasion. Our data demonstrated that Bif-1 is frequently expressed in hepatocellular carcinoma. Overexpression of Bif-1 is a new independent prognostic marker, which is associated with poor differentiation as well as shortened overall survival.
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Affiliation(s)
- Rengen Fan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China
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