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1
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Pimentel JM, Zhou JY, Wu GS. Autophagy and cancer therapy. Cancer Lett 2024; 605:217285. [PMID: 39395780 DOI: 10.1016/j.canlet.2024.217285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/25/2024] [Accepted: 10/03/2024] [Indexed: 10/14/2024]
Abstract
Autophagy is an intracellular degradation process that sequesters cytoplasmic components in double-membrane vesicles known as autophagosomes, which are degraded upon fusion with lysosomes. This pathway maintains the integrity of proteins and organelles while providing energy and nutrients to cells, particularly under nutrient deprivation. Deregulation of autophagy can cause genomic instability, low protein quality, and DNA damage, all of which can contribute to cancer. Autophagy can also be overactivated in cancer cells to aid in cancer cell survival and drug resistance. Emerging evidence indicates that autophagy has functions beyond cargo degradation, including roles in tumor immunity and cancer stem cell survival. Additionally, autophagy can also influence the tumor microenvironment. This feature warrants further investigation of the role of autophagy in cancer, in which autophagy manipulation can improve cancer therapies, including cancer immunotherapy. This review discusses recent findings on the regulation of autophagy and its role in cancer therapy and drug resistance.
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Affiliation(s)
- Julio M Pimentel
- Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA; Institutional Research Academic Career Development Award Program, University of California San Diego, La Jolla, CA, 92093, USA
| | - Jun Ying Zhou
- Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, 48201, USA; Department of Oncology, Wayne State University, Detroit, MI, 48201, USA
| | - Gen Sheng Wu
- Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, 48201, USA; Department of Oncology, Wayne State University, Detroit, MI, 48201, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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2
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Jia L, Meng Q, Xu X. Autophagy-related miRNAs, exosomal miRNAs, and circRNAs in tumor progression and drug-and radiation resistance in colorectal cancer. Pathol Res Pract 2024; 263:155597. [PMID: 39426141 DOI: 10.1016/j.prp.2024.155597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 07/16/2024] [Accepted: 09/20/2024] [Indexed: 10/21/2024]
Abstract
Targeted therapies are often more tolerable than traditional cytotoxic ones. Nurses play a critical role in providing patients and caregivers with information about the disease, available therapies, and the kind, severity, and identification of any potential adverse events. By doing this, it may be possible to ensure that any adverse effects are managed quickly, maximizing the therapeutic benefit. In colorectal cancer (CRC), autophagy-related activities are significantly influenced by miRNAs and exosomal miRNAs. CRC development and treatment resistance have been associated with the cellular process of autophagy. miRNAs, which are short non-coding RNA molecules, have the ability to control the expression of genes by binding to the 3' untranslated region (UTR) of target mRNAs and either preventing or suppressing translation. It has been discovered that several miRNAs are significant regulators of CRC autophagy. By preventing autophagy, these miRNAs enhance the survival and growth of cancer cells. Exosomes are small membrane vesicles that are released by cells and include miRNAs among other bioactive compounds. Exosomes have the ability to modify recipient cells' biological processes by delivering their cargo, which includes miRNAs. It has been demonstrated that exosomal miRNAs control autophagy in CRC in both autocrine and paracrine ways. We will discuss the potential roles of miRNAs, exosomal miRNAs, and circRNAs in CRC autophagy processes and how nursing care can reduce unfavorable outcomes.
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Affiliation(s)
- Liting Jia
- Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 102413, China
| | - Qingyun Meng
- Gastroenterology Department, Qingdao Municipal Hospital, Qingdao 266000, China
| | - Xiaofeng Xu
- Thoracic Surgery, Qingdao Municipal Hospital, Qingdao 266000, China.
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3
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Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
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Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
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4
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Yousefi P, Tabibzadeh A, Jawaziri AK, Mehrjoo M, Akhavan M, Allahqoli L, Salehiniya H. Autophagy-related genes polymorphism in hepatitis B virus-associated hepatocellular carcinoma: A systematic review. Immun Inflamm Dis 2024; 12:e1182. [PMID: 38353395 PMCID: PMC10865419 DOI: 10.1002/iid3.1182] [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: 09/04/2022] [Revised: 01/19/2024] [Accepted: 01/27/2024] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) virus is the most common risk factor for developing liver malignancy. Autophagy is an essential element in human cell maintenance. Several studies have demonstrated that autophagy plays a vital role in liver cancer at different stages. In this systematic review, we intend to investigate the role of polymorphism and mutations of autophagy-related genes (ATGs) in the pathogenesis and carcinogenesis of the hepatitis B virus (HBV). MATERIALS AND METHODS The search was conducted in online databases (Web of Science, PubMed, and Scopus) using Viruses, Infections, Polymorphism, Autophagy, and ATG. The study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. RESULTS The primary search results led to 422 studies. By screening and eligibility evaluation, only four studies were relevant. The most important polymorphisms in hepatocellular carcinoma were rs2241880 in ATG16L1, rs77859116, rs510432, and rs548234 in ATG5. Furthermore, some polymorphisms are associated with an increased risk of HBV infection including, rs2241880 in ATG16L1 and rs6568431 in ATG5. CONCLUSION The current study highlights the importance of rs2241880 in ATG16L1 and rs77859116, rs510432, and rs548234 in ATG5 for HBV-induced HCC. Additionally, some mutations in ATG16L1 and ATG5 were important in risk of HBV infection. The study highlights the gap of knowledge in the field of ATG polymorphisms in HBV infection and HBV-induced HCC.
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Affiliation(s)
- Parastoo Yousefi
- Department of Virology, School of MedicineIran University of Medical SciencesTehranIran
| | - Alireza Tabibzadeh
- Department of Virology, School of MedicineIran University of Medical SciencesTehranIran
| | | | - Mohsen Mehrjoo
- Department of Biochemistry and Genetics, School of MedicineLorestan University of Medical SciencesKhorramabadIran
| | - Mandana Akhavan
- Department of Microbiology, Faculty of Medical SciencesIslamic Azad University, Arak BranchArakIran
| | - Leila Allahqoli
- Department of MidwiferyMinistry of Health and Medical EducationTehranIran
| | - Hamid Salehiniya
- Department of Epidemiology and Biostatistics, School of Health, Social Determinants of Health Research CenterBirjand University of Medical SciencesBirjandIran
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5
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Fan Z, Wan LX, Jiang W, Liu B, Wu D. Targeting autophagy with small-molecule activators for potential therapeutic purposes. Eur J Med Chem 2023; 260:115722. [PMID: 37595546 DOI: 10.1016/j.ejmech.2023.115722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/01/2023] [Accepted: 08/11/2023] [Indexed: 08/20/2023]
Abstract
Autophagy is well-known to be a lysosome-mediated catabolic process for maintaining cellular and organismal homeostasis, which has been established with many links to a variety of human diseases. Compared with the therapeutic strategy for inhibiting autophagy, activating autophagy seems to be another promising therapeutic strategy in several contexts. Hitherto, mounting efforts have been made to discover potent and selective small-molecule activators of autophagy to potentially treat human diseases. Thus, in this perspective, we focus on summarizing the complicated relationships between defective autophagy and human diseases, and further discuss the updated progress of a series of small-molecule activators targeting autophagy in human diseases. Taken together, these inspiring findings would provide a clue on discovering more small-molecule activators of autophagy as targeted candidate drugs for potential therapeutic purposes.
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Affiliation(s)
- Zhichao Fan
- Center of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin-Xi Wan
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Wei Jiang
- Center of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bo Liu
- Center of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Dongbo Wu
- Center of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Guil-Luna S, Sanchez-Montero MT, Rodríguez-Ariza A. S-Nitrosylation at the intersection of metabolism and autophagy: Implications for cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:189012. [PMID: 37918453 DOI: 10.1016/j.bbcan.2023.189012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/26/2023] [Accepted: 10/20/2023] [Indexed: 11/04/2023]
Abstract
Metabolic plasticity, which determines tumour growth and metastasis, is now understood to be a flexible and context-specific process in cancer metabolism. One of the major pathways contributing to metabolic adaptations in eucaryotic cells is autophagy, a cellular degradation and recycling process that is activated during periods of starvation or stress to maintain metabolite and biosynthetic intermediate levels. Consequently, there is a close association between the metabolic adaptive capacity of tumour cells and autophagy-related pathways in cancer. Additionally, nitric oxide regulates protein function and signalling through S-nitrosylation, a post-translational modification that can also impact metabolism and autophagy. The primary objective of this review is to provide an up-to-date overview of the role of S-nitrosylation at the intersection of metabolism and autophagy in cancer. First, we will outline the involvement of S-nitrosylation in the metabolic adaptations that occur in tumours. Then, we will discuss the multifaceted role of autophagy in cancer, the interplay between metabolism and autophagy during tumour progression, and the contribution of S-nitrosylation to autophagic dysregulation in cancer. Finally, we will present insights into relevant therapeutic aspects and discuss prospects for the future.
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Affiliation(s)
- Silvia Guil-Luna
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Department of Comparative Anatomy and Pathology, Faculty of Veterinary Medicine of Córdoba, University of Córdoba, Córdoba, Spain
| | | | - Antonio Rodríguez-Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain.
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7
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Safari F, Dadvar F. In vitro evaluation of autophagy and cell death induction in Panc1 pancreatic cancer by secretome of hAMSCs through downregulation of p-AKT/p-mTOR and upregulation of p-AMPK/ULK1 signal transduction pathways. Tissue Cell 2023; 84:102160. [PMID: 37482027 DOI: 10.1016/j.tice.2023.102160] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/21/2023] [Accepted: 07/11/2023] [Indexed: 07/25/2023]
Abstract
One of the main causes of cancer mortality in the world is pancreatic cancer. Therapies based on stem cells are currently thought to be a hopeful option in the treatment of cancer. Herein, we intend to evaluate the antitumor effects of secretome of human amniotic mesenchymal stromal cells (hAMSCs) on autophagy and cell death induction in Panc1 pancreatic cancer cells. We adopted a co-culture system using Transwell 6-well plates and after 72 h, hAMSCs-treated Panc1 cancer cells were analyzed using quantitative real time PCR (qRT-PCR), flow cytometry, western blot, MTT assay, and DAPI staining. Based on our results, the microtubule-associated protein 1 light chain 3 (LC3) conversion from LC3-I to LC3-II and the upregulation of autophagy-related proteins expression including Beclin1, Atg7, and Atg12 were detected in hAMSCs-treated Panc1 cells. Furthermore, the level of phosphorylated proteins such as Unc-51-like kinase 1 (ULK1), AMP activated protein kinase (AMPK), AKT, and mTOR changed. Apoptotic cell death was also induced via the elevation of Bax and Caspase 3 expression and inhibition of Bcl-2. Our findings showed that secretome of hAMSCs induces autophagy and cell death in Panc1 cancer cells. However, more experiments will be needed to identify more details about the associated mechanisms.
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Affiliation(s)
- Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
| | - Faezeh Dadvar
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
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8
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Yamaguchi N, Sakaguchi T, Isomoto H, Inamine T, Ueda H, Fukuda D, Ohnita K, Kanda T, Kurumi H, Matsushima K, Hirayama T, Yashima K, Tsukamoto K. ATG16L1 and ATG12 Gene Polymorphisms Are Involved in the Progression of Atrophic Gastritis. J Clin Med 2023; 12:5384. [PMID: 37629426 PMCID: PMC10455120 DOI: 10.3390/jcm12165384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/08/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection causes a progression to atrophic gastritis and results in gastric cancer. Cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is injected into gastric epithelial cells using the type IV secretion system. On the other hand, gastric epithelial cells degrade CagA using an autophagy system, which is strictly regulated by the autophagy-related (ATG) genes. This study aimed to identify SNPs in ATG5, ATG10, ATG12, and ATG16L1 associated with gastric mucosal atrophy (GMA). Here, two-hundred H. pylori-positive participants without gastric cancer were included. The degree of GMA was evaluated via the pepsinogen method. Twenty-five SNPs located in the four candidate genes were selected as tag SNPs. The frequency of each SNP between the GMA and the non-GMA group was evaluated. The rs6431655, rs6431659, and rs4663136 in ATG16L1 and rs26537 in ATG12 were independently associated with GMA. Of these four SNPs, the G/G genotype of rs6431659 in ATG16L1 has the highest odd ratio (Odds ratio = 3.835, 95% confidence intervals = 1.337-1.005, p = 0.008). Further functional analyses and prospective analyses with a larger sample size are required.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Tatsuo Inamine
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Haruka Ueda
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Science, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki 850-0045, Japan
| | - Tsutomu Kanda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Hiroki Kurumi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kazuo Yashima
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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9
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Wang F, Peters R, Jia J, Mudd M, Salemi M, Allers L, Javed R, Duque TLA, Paddar MA, Trosdal ES, Phinney B, Deretic V. ATG5 provides host protection acting as a switch in the atg8ylation cascade between autophagy and secretion. Dev Cell 2023; 58:866-884.e8. [PMID: 37054706 PMCID: PMC10205698 DOI: 10.1016/j.devcel.2023.03.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/26/2023] [Accepted: 03/20/2023] [Indexed: 04/15/2023]
Abstract
ATG5 is a part of the E3 ligase directing lipidation of ATG8 proteins, a process central to membrane atg8ylation and canonical autophagy. Loss of Atg5 in myeloid cells causes early mortality in murine models of tuberculosis. This in vivo phenotype is specific to ATG5. Here, we show using human cell lines that absence of ATG5, but not of other ATGs directing canonical autophagy, promotes lysosomal exocytosis and secretion of extracellular vesicles and, in murine Atg5fl/fl LysM-Cre neutrophils, their excessive degranulation. This is due to lysosomal disrepair in ATG5 knockout cells and the sequestration by an alternative conjugation complex, ATG12-ATG3, of ESCRT protein ALIX, which acts in membrane repair and exosome secretion. These findings reveal a previously undescribed function of ATG5 in its host-protective role in murine experimental models of tuberculosis and emphasize the significance of the branching aspects of the atg8ylation conjugation cascade beyond the canonical autophagy.
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Affiliation(s)
- Fulong Wang
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Ryan Peters
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Jingyue Jia
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Michal Mudd
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Michelle Salemi
- Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, Davis, CA 95616, USA
| | - Lee Allers
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Ruheena Javed
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Thabata L A Duque
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Masroor A Paddar
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Einar S Trosdal
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
| | - Brett Phinney
- Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, Davis, CA 95616, USA
| | - Vojo Deretic
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA.
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10
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Du YX, Mamun AA, Lyu AP, Zhang HJ. Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer. Int J Mol Sci 2023; 24:7310. [PMID: 37108476 PMCID: PMC10138367 DOI: 10.3390/ijms24087310] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/03/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.
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Affiliation(s)
| | | | - Ai-Ping Lyu
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong SAR, China; (Y.-X.D.); (A.A.M.)
| | - Hong-Jie Zhang
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong SAR, China; (Y.-X.D.); (A.A.M.)
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11
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Ahmadi-Dehlaghi F, Mohammadi P, Valipour E, Pournaghi P, Kiani S, Mansouri K. Autophagy: A challengeable paradox in cancer treatment. Cancer Med 2023. [PMID: 36760166 DOI: 10.1002/cam4.5577] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/14/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023] Open
Abstract
OBJECTIVE Autophagy is an intracellular degradation pathway conserved in all eukaryotes from yeast to humans. This process plays a quality-control role by destroying harmful cellular components under normal conditions, maintaining cell survival, and establishing cellular adaptation under stressful conditions. Hence, there are various studies indicating dysfunctional autophagy as a factor involved in the development and progression of various human diseases, including cancer. In addition, the importance of autophagy in the development of cancer has been highlighted by paradoxical roles, as a cytoprotective and cytotoxic mechanism. Despite extensive research in the field of cancer, there are many questions and challenges about the roles and effects suggested for autophagy in cancer treatment. The aim of this study was to provide an overview of the paradoxical roles of autophagy in different tumors and related cancer treatment options. METHODS In this study, to find articles, a search was made in PubMed and Google scholar databases with the keywords Autophagy, Autophagy in Cancer Management, and Drug Design. RESULTS According to the investigation, some studies suggest that several advanced cancers are dependent on autophagy for cell survival, so when cancer cells are exposed to therapy, autophagy is induced and suppresses the anti-cancer effects of therapeutic agents and also results in cell resistance. However, enhanced autophagy from using anti-cancer drugs causes autophagy-mediated cell death in several cancers. Because autophagy also plays roles in both tumor suppression and promotion further research is needed to determine the precise mechanism of this process in cancer treatment. CONCLUSION We concluded in this article, autophagy manipulation may either promote or hinder the growth and development of cancer according to the origin of the cancer cells, the type of cancer, and the behavior of the cancer cells exposed to treatment. Thus, before starting treatment it is necessary to determine the basal levels of autophagy in various cancers.
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Affiliation(s)
- Farnaz Ahmadi-Dehlaghi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Biology, Payame Noor University, Tehran, Iran
| | - Parisa Mohammadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Elahe Valipour
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sarah Kiani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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12
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How ginseng regulates autophagy: Insights from multistep process. Biomed Pharmacother 2023; 158:114139. [PMID: 36580724 DOI: 10.1016/j.biopha.2022.114139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 12/03/2022] [Accepted: 12/13/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Although autophagy is a recognized contributor to the pathogenesis of human diseases, chloroquine and hydroxychloroquine are the only two FDA-approved autophagy inhibitors to date. Emerging evidence has revealed the potential therapeutic benefits of various extracts and active compounds isolated from ginseng, especially ginsenosides and their derivatives, by mediating autophagy. Mechanistically, active components from ginseng mediate key regulators in the multistep processes of autophagy, namely, initiation, autophagosome biogenesis and cargo degradation. AIM OF REVIEW To date, a review that systematically described the relationship between ginseng and autophagy is still lacking. Breakthroughs in finding the key players in ginseng-autophagy regulation will be a promising research area, and will provide positive insights into the development of new drugs based on ginseng and autophagy. KEY SCIENTIFIC CONCEPTS OF REVIEW Here, we comprehensively summarized the critical roles of ginseng-regulated autophagy in treating diseases, including cancers, neurological disorders, cardiovascular diseases, inflammation, and neurotoxicity. The dual effects of the autophagy response in certain diseases are worthy of note; thus, we highlight the complex impacts of both ginseng-induced and ginseng-inhibited autophagy. Moreover, autophagy and apoptosis are controlled by multiple common upstream signals, cross-regulate each other and affect certain diseases, especially cancers. Therefore, this review also discusses the cross-signal transduction pathways underlying the molecular mechanisms and interaction between ginseng-regulated autophagy and apoptosis.
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13
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Chen SL, Li CM, Li W, Liu QS, Hu SY, Zhao MY, Hu DS, Hao YW, Zeng JH, Zhang Y. How autophagy, a potential therapeutic target, regulates intestinal inflammation. Front Immunol 2023; 14:1087677. [PMID: 37168865 PMCID: PMC10165000 DOI: 10.3389/fimmu.2023.1087677] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 04/03/2023] [Indexed: 05/13/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a group of disorders that cause chronic inflammation in the intestines, with the primary types including ulcerative colitis and Crohn's disease. The link between autophagy, a catabolic mechanism in which cells clear protein aggregates and damaged organelles, and intestinal health has been widely studied. Experimental animal studies and human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation and other aspects. However, few articles have summarized and discussed the pathways by which autophagy improves or exacerbates IBD. Here, we review how autophagy alleviates IBD through the specific genes (e.g., ATG16L1, IRGM, NOD2 and LRRK2), crosstalk of multiple phenotypes with autophagy (e.g., Interaction of autophagy with endoplasmic reticulum stress, intestinal antimicrobial defense and apoptosis) and autophagy-associated signaling pathways. Moreover, we briefly discuss the role of autophagy in colorectal cancer and current status of autophagy-based drug research for IBD. It should be emphasized that autophagy has cell-specific and environment-specific effects on the gut. One of the problems of IBD research is to understand how autophagy plays a role in intestinal tract under specific environmental factors. A better understanding of the mechanism of autophagy in the occurrence and progression of IBD will provide references for the development of therapeutic drugs and disease management for IBD in the future.
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Affiliation(s)
- Shuang-Lan Chen
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chun-Meng Li
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei Li
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qing-Song Liu
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuang-Yuan Hu
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mao-Yuan Zhao
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dong-Sen Hu
- Department of Reproductive Medicine, Chengdu Xinan Women’s Hospital, Chengdu, China
| | - Yan-Wei Hao
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jin-Hao Zeng
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Jin-Hao Zeng, ; Yi Zhang,
| | - Yi Zhang
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Jin-Hao Zeng, ; Yi Zhang,
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14
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Xu W, Zhao D, Huang X, Zhang M, Yin M, Liu L, Wu H, Weng Z, Xu C. The prognostic value and clinical significance of mitophagy-related genes in hepatocellular carcinoma. Front Genet 2022; 13:917584. [PMID: 35991574 PMCID: PMC9388833 DOI: 10.3389/fgene.2022.917584] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/30/2022] [Indexed: 12/21/2022] Open
Abstract
Background: Mitophagy has been found to play a significant part in the cancer process in a growing number of studies in recent years. However, there is still a lack of study on mitophagy-related genes' (MRGs) prognostic potential and clinical significance in hepatocellular carcinoma (HCC). Methods: We employed bioinformatics and statistical knowledge to examine the transcriptome data of HCC patients in the TCGA and GEO databases, with the goal of constructing a multigene predictive model. Then, we separated the patients into high- and low-risk groups based on the score. The model's dependability was determined using principal components analysis (PCA), survival analysis, independent prognostic analysis, and receiver operating characteristic (ROC) analysis. Following that, we examined the clinical correlations, pharmacological treatment sensitivity, immune checkpoint expression, and immunological correlations between patients in high and low risk groups. Finally, we evaluated the variations in gene expression between high- and low-risk groups and further analyzed the network core genes using protein-protein interaction network analysis. Results: Prognostic models were built using eight genes (OPTN, ATG12, CSNK2A2, MFN1, PGAM5, SQSTM1, TOMM22, TOMM5). During validation, the prognostic model demonstrated high reliability, indicating that it could accurately predict the prognosis of HCC patients. Additionally, we discovered that typical HCC treatment medicines had varying impacts on patients classified as high or low risk, and that individuals classified as high risk are more likely to fail immunotherapy. Additionally, the high-risk group expressed more immunological checkpoints. The immunological status of patients in different risk categories varies as well, and patients with a high-risk score have a diminished ability to fight cancer. Finally, PPI analysis identified ten related genes with potential for research. Conclusion: Our prognostic model had good and reliable predictive ability, as well as clinical diagnosis and treatment guiding significance. Eight prognostic MRGs and ten network core genes merited further investigation.
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Affiliation(s)
- Wei Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dongxu Zhao
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaowei Huang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Man Zhang
- Department of Emergency Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Minyue Yin
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hongyu Wu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhen Weng
- Cyrus Tang Hematology Center and Ministry of Education Engineering Center of Hematological Disease, and the Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
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15
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Arif A, Khawar MB, Mehmood R, Abbasi MH, Sheikh N. Dichotomous role of autophagy in cancer. ASIAN BIOMED 2022; 16:111-120. [PMID: 37551378 PMCID: PMC10321184 DOI: 10.2478/abm-2022-0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Autophagy is an evolutionary conserved catabolic process that plays physiological and pathological roles in a cell. Its effect on cellular metabolism, the proteome, and the number and quality of organelles, diversely holds the potential to alter cellular functions. It acts paradoxically in cancer as a tumor inhibitor as well as a tumor promoter. In the early stage of tumorigenesis, it prevents tumor initiation by the so-called "quality control mechanism" and suppresses cancer progression. For late-staged tumors that are exposed to stress, it acts as a vibrant process of degradation and recycling that promotes cancer by facilitating metastasis. Despite this dichotomy, the crucial role of autophagy is evident in cancer, and associated with mammalian targets of rapamycin (mTOR), p53, and Ras-derived major cancer networks. Irrespective of the controversy regarding autophagic manipulation, promotion and suppression of autophagy act as potential therapeutic targets in cancer treatment and may provide various anticancer therapies.
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Affiliation(s)
- Amin Arif
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
| | - Muhammad Babar Khawar
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
- Department of Zoology, University of Narowal, Narowal51750, Pakistan
| | - Rabia Mehmood
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
| | - Muddasir Hassan Abbasi
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
- Department of Zoology, University of Okara, Okara56130, Pakistan
| | - Nadeem Sheikh
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
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16
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Novel Effects of Statins on Cancer via Autophagy. Pharmaceuticals (Basel) 2022; 15:ph15060648. [PMID: 35745567 PMCID: PMC9228383 DOI: 10.3390/ph15060648] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 02/05/2023] Open
Abstract
Cancer is one of the main causes of death globally. Most of the molecular mechanisms underlying cancer are marked by complex aberrations that activate the critical cell-signaling pathways that play a pivotal role in cell metabolism, tumor development, cytoskeletal reorganization, and metastasis. The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway is one of the main signaling pathways involved in carcinogenesis and metastasis. Autophagy, a cellular pathway that delivers cytoplasmic components to lysosomes for degradation, plays a dual role in cancer, as either a tumor promoter or a tumor suppressor, depending on the stage of the carcinogenesis. Statins are the group of drugs of choice to lower the level of low-density lipoprotein (LDL) cholesterol in the blood. Experimental and clinical data suggest the potential of statins in the treatment of cancer. In vitro and in vivo studies have demonstrated the molecular mechanisms through which statins inhibit the proliferation and metastasis of cancer cells in different types of cancer. The anticancer properties of statins have been shown to result in the suppression of tumor growth, the induction of apoptosis, and autophagy. This literature review shows the dual role of the autophagic process in cancer and the latest scientific evidence related to the inducing effect exerted by statins on autophagy, which could explain their anticancer potential.
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17
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Wang W, Yu ZY, Song RH, He ST, Shi LF, Zhang JA. Polymorphisms of ATG5 Gene Are Associated with Autoimmune Thyroid Diseases, Especially Thyroid Eye Disease. J Immunol Res 2022; 2022:3881417. [PMID: 35518570 PMCID: PMC9064513 DOI: 10.1155/2022/3881417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 12/06/2021] [Accepted: 03/30/2022] [Indexed: 11/18/2022] Open
Abstract
Objective To explore the association of ATG5 gene polymorphisms with autoimmune thyroid diseases (AITDs) including Hashimoto's thyroiditis (HT) and Graves' illness (GD) as well as their clinical features. Methods rs6568431, rs548234, and rs6937876 were selected to investigate the correlation of single-nucleotide polymorphisms of ATG5 gene with AITDs. Their frequencies in 824 AITD patients, including 271 HT patients and 553 GD patients, and 764 healthy controls were tested using both ligase detection reaction and multiplex polymerase chain reaction. Results Allele A frequency of rs6568431 in AITDs patients (p = 0.016, OR = 1.201, 95% CI = 1.034 - 1.394) and allele G frequency of rs6937876 in AITDs patients (p = 0.009, OR = 1.223, 95% CI = 1.052 - 1.422) and in GD patients (p = 0.009, OR = 1.247, 95% CI = 1.056 - 1.473) were significantly higher than those in the healthy controls. The frequency of G allele (p = 5.42E - 18, OR = 0.242, 95% CI = 0.173 - 0.339) of rs6937876 was significantly higher in GD patients with ophthalmopathy. However, no relationship was found between family history, age onset, and the three SNPs. Conclusion The study is the first to reveal the association between AITDs and ATG5 polymorphisms, and ATG5 gene is considered as a predisposing gene to AITDs, especially GDs.
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Affiliation(s)
- Wen Wang
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, China 201318
- Department of Endocrinology, Jinshan Hospital of Fudan University, No. 1508 Longhang Road, Jinshan District, Shanghai, China 201508
| | - Zheng-yao Yu
- Department of Otolaryngology, Shanghai Songjiang District Central Hospital, No. 746 Middle Zhongshan Road, Shanghai, China 201600
| | - Rong-hua Song
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, China 201318
| | - Shuang-tao He
- Department of Endocrinology, Jinshan Hospital of Fudan University, No. 1508 Longhang Road, Jinshan District, Shanghai, China 201508
| | - Liang-feng Shi
- Department of Endocrinology, Jinshan Hospital of Fudan University, No. 1508 Longhang Road, Jinshan District, Shanghai, China 201508
| | - Jin-an Zhang
- Department of Endocrinology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong District, Shanghai, China 201318
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18
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The Role of Macroautophagy and Chaperone-Mediated Autophagy in the Pathogenesis and Management of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14030760. [PMID: 35159028 PMCID: PMC8833636 DOI: 10.3390/cancers14030760] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is a major health problem with the second highest mortality among all cancers and a continuous increase worldwide. HCC is highly resistant to available chemotherapeutic agents, leaving patients with no effective therapeutic option and a poor prognosis. Although an increasing number of studies have elucidated the potential role of autophagy underlying HCC, the complete regulation is far from understood. The different forms of autophagy constitute important cell survival mechanisms that could prevent hepatocarcinogenesis by limiting hepatocyte death and the associated hepatitis and fibrosis at early stages of chronic liver diseases. On the other hand, at late stages of hepatocarcinogenesis, they could support the malignant transformation of (pre)neoplastic cells by facilitating their survival. Abstract Hepatocarcinogenesis is a long process with a complex pathophysiology. The current therapeutic options for HCC management, during the advanced stage, provide short-term survival ranging from 10–14 months. Autophagy acts as a double-edged sword during this process. Recently, two main autophagic pathways have emerged to play critical roles during hepatic oncogenesis, macroautophagy and chaperone-mediated autophagy. Mounting evidence suggests that upregulation of macroautophagy plays a crucial role during the early stages of carcinogenesis as a tumor suppressor mechanism; however, it has been also implicated in later stages promoting survival of cancer cells. Nonetheless, chaperone-mediated autophagy has been elucidated as a tumor-promoting mechanism contributing to cancer cell survival. Moreover, the autophagy pathway seems to have a complex role during the metastatic stage, while induction of autophagy has been implicated as a potential mechanism of chemoresistance of HCC cells. The present review provides an update on the role of autophagy pathways in the development of HCC and data on how the modulation of the autophagic pathway could contribute to the most effective management of HCC.
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Koustas E, Trifylli EM, Sarantis P, Kontolatis NI, Damaskos C, Garmpis N, Vallilas C, Garmpi A, Papavassiliou AG, Karamouzis MV. The Implication of Autophagy in Gastric Cancer Progression. Life (Basel) 2021; 11:life11121304. [PMID: 34947835 PMCID: PMC8705750 DOI: 10.3390/life11121304] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis, and strategies for clinical management. However, many gastric tumors appear to be resistant to current chemotherapeutic agents. Moreover, a significant number of gastric cancer patients, with a lack of optimal treatment strategies, have reduced survival. In recent years, multiple research data have highlighted the importance of autophagy, an essential catabolic process of cytoplasmic component digestion, in cancer. The role of autophagy as a tumor suppressor or tumor promoter mechanism remains controversial. The multistep nature of the autophagy process offers a wide array of targetable points for designing novel chemotherapeutic strategies. The purpose of this review is to summarize the current knowledge regarding the interplay between gastric cancer development and the autophagy process and decipher the role of autophagy in this kind of cancer. A plethora of different agents that direct or indirect target autophagy may be a novel therapeutic approach for gastric cancer patients.
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Affiliation(s)
- Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
- Correspondence:
| | - Eleni-Myrto Trifylli
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Nikolaos I. Kontolatis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Christos Damaskos
- Renal Transplantation Unit, ‘Laiko’ General Hospital, 11527 Athens, Greece;
- ‘N.S. Christeas’ Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Garmpis
- ‘N.S. Christeas’ Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Second Department of Propedeutic Surgery, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christos Vallilas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Anna Garmpi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.-M.T.); (P.S.); (N.I.K.); (C.V.); (A.G.P.); (M.V.K.)
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20
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Lan SH, Lin SC, Wang WC, Yang YC, Lee JC, Lin PW, Chu ML, Lan KY, Zuchini R, Liu HS, Wu SY. Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer. Front Oncol 2021; 11:738144. [PMID: 34737955 PMCID: PMC8560741 DOI: 10.3389/fonc.2021.738144] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/04/2021] [Indexed: 12/18/2022] Open
Abstract
Many studies reported that microRNAs (miRNAs) target autophagy-related genes to affect carcinogenesis, however, autophagy-deficiency-related miRNA dysfunction in cancer development remains poorly explored. During autophagic progression, we identified miR-449a as the most up-regulated miRNA. MiR-449a expression was low in the tumor parts of CRC patient specimens and inversely correlated with tumor stage and metastasis with the AUC (area under the curve) of 0.899 and 0.736 as well as poor overall survival rate, indicating that miR-449a has the potential to be a prognostic biomarker. In the same group of CRC specimens, low autophagic activity (low Beclin 1 expression and high p62 accumulation) was detected, which was significantly associated with miR-449a expression. Mechanistic studies disclosed that autophagy upregulates miR-449a expression through degradation of the coactivator p300 protein which acetylates the transcription factor Forkhead Box O1 (FoxO1). Unacetylated FoxO1 translocated to the nucleus and bound to the miR-449a promoter to drive gene expression. Either activation of autophagy by the inducer or overexpression of exogenous miR-449a decreases the expression of target gene LEF-1 and cyclin D1, which lead to decreased proliferation, colony formation, migration, and invasion of CRC cells. Autophagy-miR-449a-tartet genes mediated suppression of tumor formation was further confirmed in the xenograft mouse model. In conclusion, this study reveals a novel mechanism wherein autophagy utilizes miR-449a-LEF1-cyclin D1 axis to suppress CRC tumorigenesis. Our findings open a new avenue toward prognosis and treatment of CRC patients by manipulating autophagy-miR-449a axis.
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Affiliation(s)
- Sheng-Hui Lan
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shu-Ching Lin
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Chen Wang
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Chan Yang
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jenq-Chang Lee
- Department of Surgery, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Pei-Wen Lin
- Center for Cancer Research, Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Man-Ling Chu
- Center for Cancer Research, Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kai-Ying Lan
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Roberto Zuchini
- Department of Gastroenterology, Hospital Centro Médico, Guatemala City, Guatemala
| | - Hsiao-Sheng Liu
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center for Cancer Research, Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Master of Science Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shan-Ying Wu
- Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
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21
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Liu PF, Shu CW, Yang HC, Lee CH, Liou HH, Ger LP, Tzeng YDT, Wang WC. Combined Evaluation of MAP1LC3B and SQSTM1 for Biological and Clinical Significance in Ductal Carcinoma of Breast Cancer. Biomedicines 2021; 9:biomedicines9111514. [PMID: 34829743 PMCID: PMC8615094 DOI: 10.3390/biomedicines9111514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/06/2021] [Accepted: 10/17/2021] [Indexed: 01/18/2023] Open
Abstract
Breast cancer is the leading cause of cancer death in women worldwide. The microtubule-associated protein light chain 3B (MAP1LC3B) and adaptor sequestosome 1 (SQSTM1) are two major markers for autophagy. Increased protein levels of MAP1LC3B and SQSTM1 are considered to be causes of autophagy inhibition or activation in various types of cancers. However, the roles of MAP1LC3B and SQSTM1 in breast cancer are still not clear. Using a tissue microarray from 274 breast invasive ductal carcinoma (IDC) patients, we found that tumor tissues showed higher protein levels of MAP1LC3B and cytoplasmic SQSTM1 in comparison to those in adjacent normal tissues. Moreover, high levels of MAP1LC3B were associated with better survival, including disease-specific survival and disease-free survival (DFS) in IDC patients. Furthermore, high co-expression of MAP1LC3B and SQSTM1 was significantly associated with better DFS in IDC patients. Astonishingly, the autophagy inhibitor accumulated the protein levels of MAP1LC3B/SQSTM1 and enhanced the cytotoxic effects of cisplatin and paclitaxel in MCF7 and BT474 breast cancer cell lines, implying that autophagy inhibition might result in poor prognosis and chemosensitivity in IDC. Taken together, high co-expression of MAP1LC3B and SQSTM1 might serve as a potential diagnostic and prognostic biomarker for IDC patients.
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Affiliation(s)
- Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.-F.L.); (C.-H.L.)
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Chih-Wen Shu
- Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan;
| | - Hsiu-Chen Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan; (H.-C.Y.); (H.-H.L.); (L.-P.G.)
| | - Cheng-Hsin Lee
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.-F.L.); (C.-H.L.)
| | - Huei-Han Liou
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan; (H.-C.Y.); (H.-H.L.); (L.-P.G.)
| | - Luo-Ping Ger
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan; (H.-C.Y.); (H.-H.L.); (L.-P.G.)
| | - Yen-Dun Tony Tzeng
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
- Correspondence: (Y.-D.T.T.); (W.-C.W.); Tel.: +886-07-3422121-73008 (Y.-D.T.T.); +886-06-2812811-57112 (W.-C.W.)
| | - Wen-Ching Wang
- Department of General Surgery, Chi Mei Medical Center, Tainan 71004, Taiwan
- Correspondence: (Y.-D.T.T.); (W.-C.W.); Tel.: +886-07-3422121-73008 (Y.-D.T.T.); +886-06-2812811-57112 (W.-C.W.)
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Autophagy in Tumor Immunity and Viral-Based Immunotherapeutic Approaches in Cancer. Cells 2021; 10:cells10102672. [PMID: 34685652 PMCID: PMC8534833 DOI: 10.3390/cells10102672] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 01/09/2023] Open
Abstract
Autophagy is a fundamental catabolic process essential for the maintenance of cellular and tissue homeostasis, as well as directly contributing to the control of invading pathogens. Unsurprisingly, this process becomes critical in supporting cellular dysregulation that occurs in cancer, particularly the tumor microenvironments and their immune cell infiltration, ultimately playing a role in responses to cancer therapies. Therefore, understanding "cancer autophagy" could help turn this cellular waste-management service into a powerful ally for specific therapeutics. For instance, numerous regulatory mechanisms of the autophagic machinery can contribute to the anti-tumor properties of oncolytic viruses (OVs), which comprise a diverse class of replication-competent viruses with potential as cancer immunotherapeutics. In that context, autophagy can either: promote OV anti-tumor effects by enhancing infectivity and replication, mediating oncolysis, and inducing autophagic and immunogenic cell death; or reduce OV cytotoxicity by providing survival cues to tumor cells. These properties make the catabolic process of autophagy an attractive target for therapeutic combinations looking to enhance the efficacy of OVs. In this article, we review the complicated role of autophagy in cancer initiation and development, its effect on modulating OVs and immunity, and we discuss recent progress and opportunities/challenges in targeting autophagy to enhance oncolytic viral immunotherapy.
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Shi D, Zhang Y, Mao T, Liu D, Liu W, Luo B. MiR-BART2-3p targets Unc-51-like kinase 1 and inhibits cell autophagy and migration in Epstein-Barr virus-associated gastric cancer. Virus Res 2021; 305:198567. [PMID: 34555439 DOI: 10.1016/j.virusres.2021.198567] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 12/29/2022]
Abstract
ULK1 (Unc-51-like kinase 1) is an evolutionarily conserved serine/threonine kinase that plays a central role in the regulation of autophagy. ULK1 is associated with prognosis for metastasis and survival in several tumors. However, its relationship with Epstein-Barr virus (EBV) has not been studied. We found that the expression of ULK1 in EBV-associated gastric cancer cells was lower than that in EBV-negative gastric cancer cells. Further, a luciferase reporter gene assay showed that miR-BART2-3p directly targets ULK1. EBV-miR-BART2-3p attenuated endogenous protein expression levels of some autophagy-related genes. MiR-BART2-3p could thus be involved in the regulation of autophagy. Most important, our research indicates that miR-BART2-3p targets ULK1, resulting in downregulation of epithelial-mesenchymal transformation (EMT) -associated marker proteins and reducing EMT and cell migration. Our study shows that modulation of ULK1 is the likely mechanism by which miR-BART2-3p participates in the regulation of autophagy and cancer cell migration.
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Affiliation(s)
- Duo Shi
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Yan Zhang
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China; Department of Clinical Laboratory, Zibo Central Hospital, ZiBo, 255000, China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Dandan Liu
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Wen Liu
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Bing Luo
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
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Xu Y, Chen J, Wang M, Yu R, Zou W, Shen W. Mechanism of lncRNA-ANRIL/miR-181b in autophagy of cardiomyocytes in mice with uremia by targeting ATG5. PLoS One 2021; 16:e0256734. [PMID: 34469488 PMCID: PMC8410126 DOI: 10.1371/journal.pone.0256734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 08/13/2021] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVES This study is to investigate whether the cardiac microvascular endothelial cells (CMECs) can regulate the autophagy of cardiomyocytes (CMs) by secreting lncRNA-ANRIL/miR-181b exosomes, thus participating in the occurrence of uremic cardiovascular disease (CVD). METHODS A 5/6 nephrectomy uremia model was established, with the mice injected with ANRIL-shRNA lentivirus vector, miR-181b agomir, and related control reagents, containing the serum creatinine and urea nitrogen measured. The renal tissue sections of mice were stained with Periodic Acid-Schiff (PAS), TUNEL, and Hematoxylin-Eosin (HE) performed on myocardial tissue sections of mice. ANRIL-shRNA, miR-181b mimics, and related control reagents were transfected into CMECs, in which the exosomes were extracted and co-cultured with CMs. The expressions of ANRIL, miR-181b and ATG5 were detected by qRT-PCR, and the expressions of autophagy related proteins by Western blot, as well as the binding of ANRIL and miR-181b by the double luciferase reporter gene experiment. RESULTS ANRIL down-regulation or miR-181b up-regulation can increase the weight of mice with uremia, as well as the expressions of p62 and miR-181b, and reduce the content of serum creatinine and urea nitrogen, the damage of kidney and myocardial tissues, the number of apoptotic cells in myocardial tissues, as well as the expressions of ANRIL, ATG5, Beclin1, and LC3. CMs can absorb the exosomes of CMECs. Compared with IS+ CMEC-Exo group, the expressions of ANRIL and ATG5 in CMs of IS+ CMEC-Exo + sh lncRNA ANRIL and IS+CMEC-Exo+miR-181b mimics groups was down-regulated, as well as the expressions of ATG5, Beclin1, and LC3, while miR-181b expression was up-regulated as well as P62 expression. CONCLUSIONS CMECs can regulate autophagy of CMs by releasing exosomes containing ANRIL and miR-181b.
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Affiliation(s)
- Ying Xu
- Department of Urology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
| | - Jing Chen
- Department of Urology, Tongde Hospital of Zhejiang Province, Zhejiang, China
| | - Minmin Wang
- Department of Nephrology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
| | - Rizhen Yu
- Department of Nephrology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
| | - Wenly Zou
- Department of Nephrology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
| | - Wei Shen
- Department of Nephrology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
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25
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Jandrey EHF, Bezerra M, Inoue LT, Furnari FB, Camargo AA, Costa ÉT. A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas. Front Oncol 2021; 11:652133. [PMID: 34178638 PMCID: PMC8222785 DOI: 10.3389/fonc.2021.652133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
There are no effective strategies for the successful treatment of glioblastomas (GBM). Current therapeutic modalities effectively target bulk tumor cells but leave behind marginal GBM cells that escape from the surgical margins and radiotherapy field, exhibiting high migratory phenotype and resistance to all available anti-glioma therapies. Drug resistance is mostly driven by tumor cell plasticity: a concept associated with reactivating transcriptional programs in response to adverse and dynamic conditions from the tumor microenvironment. Autophagy, or "self-eating", pathway is an emerging target for cancer therapy and has been regarded as one of the key drivers of cell plasticity in response to energy demanding stress conditions. Many studies shed light on the importance of autophagy as an adaptive mechanism, protecting GBM cells from unfavorable conditions, while others recognize that autophagy can kill those cells by triggering a non-apoptotic cell death program, called 'autophagy cell death' (ACD). In this review, we carefully analyzed literature data and conclude that there is no clear evidence indicating the presence of ACD under pathophysiological settings in GBM disease. It seems to be exclusively induced by excessive (supra-physiological) stress signals, mostly from in vitro cell culture studies. Instead, pre-clinical and clinical data indicate that autophagy is an emblematic example of the 'dark-side' of a rescue pathway that contributes profoundly to a pro-tumoral adaptive response. From a standpoint of treating the real human disease, only combinatorial therapy targeting autophagy with cytotoxic drugs in the adjuvant setting for GBM patients, associated with the development of less toxic and more specific autophagy inhibitors, may inhibit adaptive response and enhance the sensibility of glioma cells to conventional therapies.
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Affiliation(s)
| | - Marcelle Bezerra
- Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil
| | | | - Frank B. Furnari
- Ludwig Institute for Cancer Research, University of California San Diego (UCSD), San Diego, CA, United States
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Abstract
Autophagy is a regulated mechanism that removes unnecessary or dysfunctional cellular components and recycles metabolic substrates. In response to stress signals in the tumour microenvironment, the autophagy pathway is altered in tumour cells and immune cells - thereby differentially affecting tumour progression, immunity and therapy. In this Review, we summarize our current understanding of the immunologically associated roles and modes of action of the autophagy pathway in cancer progression and therapy, and discuss potential approaches targeting autophagy to enhance antitumour immunity and improve the efficacy of current cancer therapy.
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Affiliation(s)
- Houjun Xia
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
| | - Weiping Zou
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
- Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
- Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
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Wu M, Chen B, Pan X, Su J. Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer. Cancer Manag Res 2020; 12:13527-13540. [PMID: 33414645 PMCID: PMC7783202 DOI: 10.2147/cmar.s278354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Autophagy-related proteins (ATG) play a crucial role in autophagy. Recently, the functions of autophagy in cancer have been gathering attention. However, the prognostic value of ATGs in gastric cancer (GC) has not been explored. Methods The Kaplan–Meier plotter (KM plotter) online database was used to examine the value of ATGs gene expression levels in overall survival (OS) prediction in GC patients with different clinical stage, differentiation, gender, HER2 status, and therapeutic strategy. In vitro experiments applied VE-822, an effective GC treatment, to assess cell migration and proliferation in gastric mucosa epithelial cells, and real-time PCR was used to measure alterations of autophagy-related gene expression. Results High ATG3, ATG4C, ATG5, and ATG10 mRNA levels were associated with good OS, while increased ATG4B, ATG7, ATG12, ATG16L1, and TECPR1 mRNA levels related to unfavorable OS in patients with GC. ATG12 overexpression had different effects on OS due to high levels of heterogeneity. High ATG12 expression was correlated with good OS in female patients with GC and with bad OS for male patients. Additionally, the increased ATG12 expression was more likely to get a satisfactory OS in patients who underwent surgery alone but was associated with poor OS for patients treated with 5-FU adjuvant. In addition, elevated TECPR1 expression was related to favorable OS for patients with poorly differentiated type, while for patients with moderate differentiation, it was relevant to poor OS. The in vitro experiments showed that berzosertib could significantly inhibit the migration and proliferation of human gastric mucosa epithelial cells, and further real-time PCR assessment of ATG expressions partially coincided with the bioinformation analysis above. Conclusion These results indicate that individual ATGs have unique prognostic significance interpreted using Kaplan–Meier plotter analysis and in vitro experiments, and this may help guide clinical therapeutic strategy and promote OS by individualizing therapy for GC patients.
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Affiliation(s)
- Minmin Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
| | - Xiaodong Pan
- Department of Transplantation Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
| | - Jiadong Su
- Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
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Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy. Proc Natl Acad Sci U S A 2020; 117:25543-25552. [PMID: 32999071 DOI: 10.1073/pnas.2007622117] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.
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29
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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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Kiruthiga C, Devi KP, Nabavi SM, Bishayee A. Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12030562. [PMID: 32121322 PMCID: PMC7139730 DOI: 10.3390/cancers12030562] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death.
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Affiliation(s)
- Chandramohan Kiruthiga
- Department of Biotechnology, Alagappa University (Science Campus), Karaikudi 630 003, Tamil Nadu, India;
| | - Kasi Pandima Devi
- Department of Biotechnology, Alagappa University (Science Campus), Karaikudi 630 003, Tamil Nadu, India;
- Correspondence: (K.P.D.); or (A.B.); Tel.: +91-4565223325 (K.P.D.); +1-941-782-5950 (A.B.)
| | - Seyed M. Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran;
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
- Correspondence: (K.P.D.); or (A.B.); Tel.: +91-4565223325 (K.P.D.); +1-941-782-5950 (A.B.)
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31
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Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer 2020; 19:12. [PMID: 31969156 PMCID: PMC6975070 DOI: 10.1186/s12943-020-1138-4] [Citation(s) in RCA: 982] [Impact Index Per Article: 196.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 01/16/2020] [Indexed: 12/19/2022] Open
Abstract
Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.
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Affiliation(s)
- Xiaohua Li
- Henan Provincial People's Hospital, Zhengzhou, 450003, China.,Henan Eye Hospital, Henan Eye Institute, Henan Key Laboratory of Ophthalmology and Visual Science, Zhengzhou, 450003, China.,People's Hospital of Zhengzhou University, Zhengzhou, 450003, China.,People's Hospital of Henan University, Zhengzhou, 450003, China
| | - Shikun He
- Ophthalmology Optometry Centre, Peking University People's Hospital, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.,Department of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Binyun Ma
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA. .,Department of Medicine/Hematology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA.
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Ren J, Sui H, Fang F, Li Q, Li B. The application of Apc Min/+ mouse model in colorectal tumor researches. J Cancer Res Clin Oncol 2019; 145:1111-1122. [PMID: 30887153 DOI: 10.1007/s00432-019-02883-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 02/28/2019] [Indexed: 12/11/2022]
Abstract
PURPOSE ApcMin/+ mouse is an excellent animal model bearing multiple intestinal neoplasia, used to simulate human familial adenomatous polyposis and colorectal tumors. The key point of this model is the mutation of Apc gene, which is a significant tumor-suppressor gene in the Wnt signaling pathway. There are also some other possible mechanisms responsible for the development of colorectal tumors in the ApcMin/+ mouse model, such as tumor-associated signaling pathways activation, the changes of tumor-related genes, and the involvement of some related proteins or molecules. METHODS The relevant literatures about ApcMin/+ mouse model from PUBMED databases are reviewed in this study. RESULTS In recent years, increasing studies have focused on the application of ApcMin/+ mouse model in colorectal tumor, trying to find effective therapeutic targets for further use. CONCLUSION This article will give a brief review on the related molecular mechanisms of the ApcMin/+ mouse model and its application in colorectal tumor researches.
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Affiliation(s)
- Junze Ren
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, 200433, China
| | - Hua Sui
- Department of Medical Oncology, Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Fanfu Fang
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, 200433, China
| | - Qi Li
- Department of Medical Oncology, Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Bai Li
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, 200433, China.
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33
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Autophagy as a molecular target for cancer treatment. Eur J Pharm Sci 2019; 134:116-137. [PMID: 30981885 DOI: 10.1016/j.ejps.2019.04.011] [Citation(s) in RCA: 254] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 04/04/2019] [Accepted: 04/05/2019] [Indexed: 12/22/2022]
Abstract
Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.
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Yoon K, Kim N, Park Y, Kim BK, Park JH, Shin CM, Lee DH, Surh YJ. Correlation between macrophage migration inhibitory factor and autophagy in Helicobacter pylori-associated gastric carcinogenesis. PLoS One 2019; 14:e0211736. [PMID: 30742638 PMCID: PMC6370197 DOI: 10.1371/journal.pone.0211736] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
The role of macrophage migration inhibitory factor (MIF) and autophagy in gastric cancer is not clear. We determined H. pylori infection status of the subjects and investigated the expression of MIF and autophagy markers (Atg5, LC3A and LC3B) in human gastric tissue at baseline. Then H. pylori eradication was done for H. pylori positive patients and MIF and Atg5 levels were investigated on each follow-up for both H. pylori-eradicated and H. pylori negative patients. Baseline tissue mRNA expression of MIF, Atg5, LC3A and LC3B was measured by real-time PCR in 453 patients (control 165, gastric dysplasia 82, and gastric cancer 206). Three hundred three patients (66.9%) had H. pylori infection at the time of enrollment. Only within H. pylori-positive group, MIF level was significantly elevated in patients with cancer than in control or dysplasia groups (P<0.05). LC3A and LC3B levels also showed significant differences within H. pylori-positive subgroups. H. pylori-positive dysplasia subgroup showed significantly lower (LC3A) (P<0.05) and higher (LC3B) mRNA levels (P<0.05) than in other subgroups. On follow-up, within H. pylori-eradicated group, Atg5 expression increased sequentially from control to dysplasia and cancer subgroups. Multiple linear regression showed autophagy markers (LC3A, LC3B, and Atg5) directly predicted MIF level (adjusted R2 = 0.492, P<0.001). Serial follow-up showed longitudinal increase in Atg5 level in general, with constantly higher levels in H. pylori-eradicated group than in -negative group. Intestinal metaplasia (IM) group initially showed higher Atg5 expression than the IM-negative group. However, it was reversed between the groups eventually because of the lower rate of increase in IM group. These results suggest a role of MIF and autophagy markers and their interaction in H. pylori-associated gastric carcinogenesis.
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Affiliation(s)
- Kichul Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- * E-mail:
| | - Youngmi Park
- Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Bo Kyung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
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Lin Y, Chen Y, Wang S, Ma J, Peng Y, Yuan X, Lv B, Chen W, Wei Y. Plumbagin induces autophagy and apoptosis of SMMC-7721 cells in vitro and in vivo. J Cell Biochem 2018; 120:9820-9830. [PMID: 30536473 DOI: 10.1002/jcb.28262] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 10/22/2018] [Indexed: 01/03/2023]
Abstract
Plumbagin (PL), an active naphthoquinone compound, has been demonstrated to be a potential anticancer agent. However, the underlying anticancer mechanism is not fully understood. In this study, the human hepatocellular carcinoma (HCC) SMMC-7721 cell line was studied in an in vitro model. The cell proliferation was inhibited by PL in a dose- and time-dependent manner. Electron microscopy, acridine orange staining, and immunofluorescence were used to evaluate autophagosome formation and LC3 protein expression in PL-treated SMMC-7721 cells. Real-time polymerase chain reaction and Western blot showed that PL treatment suppressed the expression of apoptosis and autophagy factors (LC3, Beclin1, Atg7, and Atg5), which are associated with tumor apoptosis and autophagy in SMMC-7721 cells. In the study of in vitro tumor nude mouse models, PL can inhibit tumor growth. Cell apoptosis and autophagy of the transplanted tumors were evaluated by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, and Western blot. In addition, in the in vivo studies of HCC cells, we found that pretreatment with the autophagy inhibitor 3-methyladenine blocked the formation of apoptosis induced by PL. In contrast, administration of the apoptosis inhibitor Z-VAD did not affect PL-induced autophagy. Taken together, our findings strongly suggest that PL is a promising drug with significant antitumor activity in HCC.
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Affiliation(s)
- Yuning Lin
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yongxin Chen
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Shengshan Wang
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jing Ma
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yue Peng
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xianling Yuan
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Beibei Lv
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Wanjun Chen
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yanfei Wei
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Park PH. Autophagy induction: a critical event for the modulation of cell death/survival and inflammatory responses by adipokines. Arch Pharm Res 2018; 41:1062-1073. [DOI: 10.1007/s12272-018-1082-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022]
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37
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Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:8023821. [PMID: 29643976 PMCID: PMC5831833 DOI: 10.1155/2018/8023821] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 11/13/2017] [Accepted: 12/14/2017] [Indexed: 12/16/2022]
Abstract
In the last two decades, accumulating evidence pointed to the importance of autophagy in various human diseases. As an essential evolutionary catabolic process of cytoplasmatic component digestion, it is generally believed that modulating autophagic activity, through targeting specific regulatory actors in the core autophagy machinery, may impact disease processes. Both autophagy upregulation and downregulation have been found in cancers, suggesting its dual oncogenic and tumor suppressor properties during malignant transformation. Identification of the key autophagy targets is essential for the development of new therapeutic agents. Despite this great potential, no therapies are currently available that specifically focus on autophagy modulation. Although drugs like rapamycin, chloroquine, hydroxychloroquine, and others act as autophagy modulators, they were not originally developed for this purpose. Thus, autophagy may represent a new and promising pharmacologic target for future drug development and therapeutic applications in human diseases. Here, we summarize our current knowledge in regard to the interplay between autophagy and malignancy in the most significant tumor types: pancreatic, breast, hepatocellular, colorectal, and lung cancer, which have been studied in respect to autophagy manipulation as a promising therapeutic strategy. Finally, we present an overview of the most recent advances in therapeutic strategies involving autophagy modulators in cancer.
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The Clinical Influence of Autophagy-Associated Proteins on Human Lung Cancer. DISEASE MARKERS 2018; 2018:8314963. [PMID: 29545906 PMCID: PMC5818951 DOI: 10.1155/2018/8314963] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 11/02/2017] [Indexed: 12/11/2022]
Abstract
Exploitation of autophagy might potentially improve therapeutic strategy. Here, we analyzed the protein expression of autophagy-associated genes including LC3A, LC3B, Beclin-1, p62, and Atg5 in 88–131 primary lung tumors by immunohistochemistry (IHC) on tissue-microarrays (TMAs). Additionally, the DNA methylation pattern of LC3A was investigated by bisulfite sequencing (BS) and methylation-specific-PCR (MSP). It turned out that the higher expression of LC3A protein was associated with adenocarcinoma compared to squamous cell carcinoma of lung (p = 0.008), positive staining of LC3B was significantly related to tumor grade (p = 0.006), and the protein expression of Beclin-1 was significantly correlated to pN stage (p = 0.041). The expression of p62 and Atg5 was however not significantly associated with any clinicopathological parameters. Downregulation of LC3A was related to DNA methylation in lung cancer cell lines, while in primary lung tumor samples, protein expression of LC3A was not significantly correlated with DNA methylation, and the methylation status of LC3A was not related to clinicopathological features. Taken together, our results suggest that autophagy-associated proteins such as LC3A, LC3B, and Beclin-1 might be potential biomarkers for subclassification, differentiation, and local metastasis in primary lung tumor, and epigenetic mechanism is partially responsible for gene silencing of LC3A in lung cancer cell lines.
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The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer. Oncotarget 2017; 7:33272-85. [PMID: 27120789 PMCID: PMC5078093 DOI: 10.18632/oncotarget.8924] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 04/10/2016] [Indexed: 01/24/2023] Open
Abstract
Breast cancer is the leading cause of cancer-associated deaths in women worldwide. Clinical biomarkers give information on disease progression and identify relevant biological pathways. A confounding factor that uncouples markers from disease outcome is the ability of tumor cells to mutate and evade clinical intervention. Therefore, we focussed on apoptotic genes that modulate tumor regression. Using gene and tissue microarray analyses, we identified an association of Bcl-2 interacting killer (Bik) with poor breast cancer prognosis. Bik prognostic ability was independent of Estrogen Receptor/Progesterone Receptor and Her2 status. Additionally, Bik was independent of anti-apoptotic Bcl-2, Bcl-xL, Mcl-1 and Bcl-w suggesting a complex mechanism of tumor promotion identified by Bik high tumors. Bik also stimulates autophagy, which can contribute to enhanced tumor fitness. We found a significant association between the autophagy marker ATG5 and Bik. Combined high expression level of ATG5 and Bik was a stronger predictor of outcome than either alone. Thus, our study identifies Bik as a novel, independent prognostic biomarker for poor outcomes in breast cancer and suggests that Bik-mediated autophagy contributes to disease recurrence.
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40
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Yang PW, Hsieh MS, Chang YH, Huang PM, Lee JM. Genetic polymorphisms of ATG5 predict survival and recurrence in patients with early-stage esophageal squamous cell carcinoma. Oncotarget 2017; 8:91494-91504. [PMID: 29207660 PMCID: PMC5710940 DOI: 10.18632/oncotarget.20793] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 07/27/2017] [Indexed: 01/08/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly disease with high risk of tumor recurrence even among patients with an early pathologic stage of tumor. In the current study, we investigate the association between 20 SNPs of the ATG5 gene and prognosis of patients with early-stage ESCC. A total of 305 patients diagnosed with early-stage ESCC were enrolled in the study and randomly assigned to a training set (n=93) or replication set (n=212). The genotypes of candidate SNPs (single nucleotide polymorphisms) within ATG5 were analyzed and correlated with the prognosis of ESCC patients. We repeatedly demonstrated that 3 SNPs in ATG5, rs1322178, rs3804329, and rs671116, were significantly correlated with the prognosis of patients with early-stage ESCC (HR[95 % CI]=2.01[1.19-3.40], p=0.009 for ATG5: rs1322178; HR[95 % CI]=1.88 [1.08-3.26], p=0.025 for ATG5:rs3804329; HR[95 % CI]=1.73[1.24-2.42], p=0.001 for ATG5:rs671116, in combined group). Both rs1322178 and rs3804329 can predict early distant metastasis of patients. Furthermore, increased expression of ATG5 was observed in ESCC tumor tissue as compared to adjacent normal tissue. Moreover, higher levels of ATG5 expression in both normal and tumor tissues exhibited a trend to correlate with poor prognosis of patients. However, the expression of ATG5 did not correlate with these 3 relevant prognostic SNPs. We concluded that hereditary genetic polymorphisms and gene expression of ATG5 can serve as prognostic predictors of patients with early-stage ESCC.
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Affiliation(s)
- Pei-Wen Yang
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Min-Shu Hsieh
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Han Chang
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Ming Huang
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jang-Ming Lee
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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41
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Bortnik S, Gorski SM. Clinical Applications of Autophagy Proteins in Cancer: From Potential Targets to Biomarkers. Int J Mol Sci 2017; 18:ijms18071496. [PMID: 28696368 PMCID: PMC5535986 DOI: 10.3390/ijms18071496] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 07/06/2017] [Accepted: 07/07/2017] [Indexed: 12/20/2022] Open
Abstract
Autophagy, a lysosome-mediated intracellular degradation and recycling pathway, plays multiple context-dependent roles in tumorigenesis and treatment resistance. Encouraging results from various preclinical studies have led to the initiation of numerous clinical trials with the intention of targeting autophagy in various cancers. Accumulating knowledge of the particular mechanisms and players involved in different steps of autophagy regulation led to the ongoing discovery of small molecule inhibitors designed to disrupt this highly orchestrated process. However, the development of validated autophagy-related biomarkers, essential for rational selection of patients entering clinical trials involving autophagy inhibitors, is lagging behind. One possible source of biomarkers for this purpose is the autophagy machinery itself. In this review, we address the recent trends, challenges and advances in the assessment of the biomarker potential of clinically relevant autophagy proteins in human cancers.
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Affiliation(s)
- Svetlana Bortnik
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
| | - Sharon M Gorski
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
- Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
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42
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Ba MC, Long H, Cui SZ, Gong YF, Yan ZF, Wang S, Wu YB. Mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. Tumour Biol 2017. [PMID: 28639902 DOI: 10.1177/1010428317711952] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Mild hyperthermia enhances anti-cancer effects of chemotherapy, but the precise biochemical mechanisms involved are not clear. This study was carried out to investigate whether mild hyperthermia sensitizes gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. In total, 20 BABL/c mice of MKN-45 human gastric cancer tumor model were divided into hyperthermia + chemotherapy group, hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group. Reactive oxygen species production and expression of autophagy-related genes Beclin1, LC3B, and mammalian target of rapamycin were determined. The relationships between tumor growth regression, expression of autophagy-related genes, and reactive oxygen species production were evaluated. Tumor size and wet weight of hyperthermia + chemotherapy group was significantly decreased relative to values from hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group ( F = 6.92, p < 0.01 and F = 5.36, p < 0.01, respectively). Reactive oxygen species production was significantly higher in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. The expression levels of Beclin1 and LC3B were significantly higher, while those of mammalian target of rapamycin were significantly lower in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. Tumor growth regression was consistent with changes in reactive oxygen species production and expression of autophagy-related genes. N-acetyl-L-cysteine inhibited changes in the expression of the autophagy-related genes and also suppressed reactive oxygen species production and tumor growth. Hyperthermia + chemotherapy increase expression of autophagy-related genes Beclin1 and LC3B, decrease expression of mammalian target of rapamycin, and concomitantly increase reactive oxygen species generation. These results strongly indicate that mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death.
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Affiliation(s)
- Ming-Chen Ba
- 1 Intracelom Hyperthermic Perfusion Therapy Center, Cancer Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Hui Long
- 2 Department of Pharmacy, Guangzhou Dermatology Institute, Guangzhou, P.R. China
| | - Shu-Zhong Cui
- 1 Intracelom Hyperthermic Perfusion Therapy Center, Cancer Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Yuan-Feng Gong
- 1 Intracelom Hyperthermic Perfusion Therapy Center, Cancer Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Zhao-Fei Yan
- 1 Intracelom Hyperthermic Perfusion Therapy Center, Cancer Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Shuai Wang
- 1 Intracelom Hyperthermic Perfusion Therapy Center, Cancer Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Yin-Bing Wu
- 1 Intracelom Hyperthermic Perfusion Therapy Center, Cancer Hospital of Guangzhou Medical University, Guangzhou, P.R. China
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43
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Yang J, Nishihara R, Zhang X, Ogino S, Qian ZR. Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer? J Diabetes Complications 2017; 31:1228-1236. [PMID: 28465145 PMCID: PMC5501176 DOI: 10.1016/j.jdiacomp.2017.04.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 04/04/2017] [Accepted: 04/10/2017] [Indexed: 12/14/2022]
Abstract
The recently rapid increase of obesity and type 2 diabetes mellitus has caused great burden to our society. A positive association between type 2 diabetes and risk of colorectal cancer has been reported by increasing epidemiological studies. The molecular mechanism of this connection remains elusive. However, type 2 diabetes may result in abnormal carbohydrate and lipid metabolism, high levels of circulating insulin, insulin growth factor-1, and adipocytokines, as well as chronic inflammation. All these factors could lead to the alteration of energy sensing pathways such as the AMP activated kinase (PRKA), mechanistic (mammalian) target of rapamycin (mTOR), SIRT1, and autophagy signaling pathways. The resulted impaired SIRT1 and autophagy signaling pathway could increase the risk of gene mutation and cancer genesis by decreasing genetic stability and DNA mismatch repair. The dysregulated mTOR and PRKA pathway could remodel cell metabolism during the growth and metastasis of cancer in order for the cancer cell to survive the unfavorable microenvironment such as hypoxia and low blood supply. Moreover, these pathways may be coupling metabolic and epigenetic alterations that are central to oncogenic transformation. Further researches including molecular pathologic epidemiologic studies are warranted to better address the precise links between these two important diseases.
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Affiliation(s)
- Juhong Yang
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Boston, MA 02215; 211 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
| | - Reiko Nishihara
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Boston, MA 02215; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis Street, Boston, MA 02115; Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis Street, Boston, MA 02115
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Boston, MA 02215; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis Street, Boston, MA 02115; Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115
| | - Zhi Rong Qian
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Boston, MA 02215.
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44
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Gozuacik D, Akkoc Y, Ozturk DG, Kocak M. Autophagy-Regulating microRNAs and Cancer. Front Oncol 2017; 7:65. [PMID: 28459042 PMCID: PMC5394422 DOI: 10.3389/fonc.2017.00065] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 03/21/2017] [Indexed: 12/12/2022] Open
Abstract
Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis. Consequently, abnormalities of autophagy are associated with a number of diseases, including Alzheimers’s disease, Parkinson’s disease, and cancer. According to the current view, autophagy seems to serve as a tumor suppressor in the early phases of cancer formation, yet in later phases, autophagy may support and/or facilitate tumor growth, spread, and contribute to treatment resistance. Therefore, autophagy is considered as a stage-dependent dual player in cancer. microRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level. miRNAs control several fundamental biological processes, and autophagy is no exception. Furthermore, accumulating data in the literature indicate that dysregulation of miRNA expression contribute to the mechanisms of cancer formation, invasion, metastasis, and affect responses to chemotherapy or radiotherapy. Therefore, considering the importance of autophagy for cancer biology, study of autophagy-regulating miRNA in cancer will allow a better understanding of malignancies and lead to the development of novel disease markers and therapeutic strategies. The potential to provide study of some of these cancer-related miRNAs were also implicated in autophagy regulation. In this review, we will focus on autophagy, miRNA, and cancer connection, and discuss its implications for cancer biology and cancer treatment.
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Affiliation(s)
- Devrim Gozuacik
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.,Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Sabanci University, Istanbul, Turkey
| | - Yunus Akkoc
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
| | - Deniz Gulfem Ozturk
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
| | - Muhammed Kocak
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
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45
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Qian HR, Yang Y. Functional role of autophagy in gastric cancer. Oncotarget 2017; 7:17641-51. [PMID: 26910278 PMCID: PMC4951239 DOI: 10.18632/oncotarget.7508] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 02/06/2016] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a highly regulated catabolic pathway responsible for the degradation of long-lived proteins and damaged intracellular organelles. Perturbations in autophagy are found in gastric cancer. In host gastric cells, autophagy can be induced by Helicobacter pylori (or H. pylori) infection, which is associated with the oncogenesis of gastric cancer. In gastric cancer cells, autophagy has both pro-survival and pro-death functions in determining cell fate. Besides, autophagy modulates gastric cancer metastasis by affecting a wide range of pathological events, including extracellular matrix (ECM) degradation, epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, and tumor microenvironment. In addition, some of the autophagy-related proteins, such as Beclin 1, microtubule-associated protein 1 light chain 3 (MAP1-LC3), and p62/sequestosome 1 (SQSTM1) have certain prognostic values for gastric cancer. In this article, we review the recent studies regarding the functional role of autophagy in gastric cancer.
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Affiliation(s)
- Hao-ran Qian
- Department of General Surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Yi Yang
- Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, PR China
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46
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Awan FM, Obaid A, Ikram A, Janjua HA. Mutation-Structure-Function Relationship Based Integrated Strategy Reveals the Potential Impact of Deleterious Missense Mutations in Autophagy Related Proteins on Hepatocellular Carcinoma (HCC): A Comprehensive Informatics Approach. Int J Mol Sci 2017; 18:ijms18010139. [PMID: 28085066 PMCID: PMC5297772 DOI: 10.3390/ijms18010139] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 11/14/2016] [Accepted: 11/16/2016] [Indexed: 12/13/2022] Open
Abstract
Autophagy, an evolutionary conserved multifaceted lysosome-mediated bulk degradation system, plays a vital role in liver pathologies including hepatocellular carcinoma (HCC). Post-translational modifications (PTMs) and genetic variations in autophagy components have emerged as significant determinants of autophagy related proteins. Identification of a comprehensive spectrum of genetic variations and PTMs of autophagy related proteins and their impact at molecular level will greatly expand our understanding of autophagy based regulation. In this study, we attempted to identify high risk missense mutations that are highly damaging to the structure as well as function of autophagy related proteins including LC3A, LC3B, BECN1 and SCD1. Number of putative structural and functional residues, including several sites that undergo PTMs were also identified. In total, 16 high-risk SNPs in LC3A, 18 in LC3B, 40 in BECN1 and 43 in SCD1 were prioritized. Out of these, 2 in LC3A (K49A, K51A), 1 in LC3B (S92C), 6 in BECN1 (S113R, R292C, R292H, Y338C, S346Y, Y352H) and 6 in SCD1 (Y41C, Y55D, R131W, R135Q, R135W, Y151C) coincide with potential PTM sites. Our integrated analysis found LC3B Y113C, BECN1 I403T, SCD1 R126S and SCD1 Y218C as highly deleterious HCC-associated mutations. This study is the first extensive in silico mutational analysis of the LC3A, LC3B, BECN1 and SCD1 proteins. We hope that the observed results will be a valuable resource for in-depth mechanistic insight into future investigations of pathological missense SNPs using an integrated computational platform.
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Affiliation(s)
- Faryal Mehwish Awan
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan.
| | - Ayesha Obaid
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan.
| | - Aqsa Ikram
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan.
| | - Hussnain Ahmed Janjua
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad 44000, Pakistan.
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de Juan-Marcos L, Escudero-Domínguez FA, Hernández-Galilea E, Cruz-González F, Follana-Neira I, González-Sarmiento R. Investigation of Association between Autophagy-Related Gene Polymorphisms and Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population. Semin Ophthalmol 2016; 33:361-366. [DOI: 10.1080/08820538.2016.1247177] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Lourdes de Juan-Marcos
- Department of Ophthalmology, University Hospital of Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | | | - Emiliano Hernández-Galilea
- Department of Ophthalmology, University Hospital of Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Fernando Cruz-González
- Department of Ophthalmology, University Hospital of Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Isora Follana-Neira
- Department of Ophthalmology, University Hospital of Salamanca, Salamanca, Spain
| | - Rogelio González-Sarmiento
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (BMCC), University of Salamanca-CSIC, Salamanca, Spain
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Lippai M, Szatmári Z. Autophagy-from molecular mechanisms to clinical relevance. Cell Biol Toxicol 2016; 33:145-168. [PMID: 27957648 DOI: 10.1007/s10565-016-9374-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 12/02/2016] [Indexed: 12/14/2022]
Abstract
Autophagy is a lysosomal degradation pathway of eukaryotic cells that is highly conserved from yeast to mammals. During this process, cooperating protein complexes are recruited in a hierarchic order to the phagophore assembly site (PAS) to mediate the elongation and closure of double-membrane vesicles called autophagosomes, which sequester cytosolic components and deliver their content to the endolysosomal system for degradation. As a major cytoprotective mechanism, autophagy plays a key role in the stress response against nutrient starvation, hypoxia, and infections. Although numerous studies reported that impaired function of core autophagy proteins also contributes to the development and progression of various human diseases such as neurodegenerative disorders, cardiovascular and muscle diseases, infections, and different types of cancer, the function of this process in human diseases remains unclear. Evidence often suggests a controversial role for autophagy in the pathomechanisms of these severe disorders. Here, we provide an overview of the molecular mechanisms of autophagy and summarize the recent advances on its function in human health and disease.
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Affiliation(s)
- Mónika Lippai
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány Péter stny. 1/C, Budapest, 1117, Hungary
| | - Zsuzsanna Szatmári
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány Péter stny. 1/C, Budapest, 1117, Hungary.
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49
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Petibone DM, Majeed W, Casciano DA. Autophagy function and its relationship to pathology, clinical applications, drug metabolism and toxicity. J Appl Toxicol 2016; 37:23-37. [PMID: 27682190 DOI: 10.1002/jat.3393] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 08/30/2016] [Accepted: 08/30/2016] [Indexed: 12/19/2022]
Abstract
Autophagy is a cellular process that facilitates nutrient turnover and removal of expended macromolecules and organelles to maintain homeostasis. The recycling of cytosolic macromolecules and damaged organelles by autophagosomes occurs through the lysosomal degradation pathway. Autophagy can also be upregulated as a prosurvival pathway in response to stress stimuli such as starvation, hypoxia or cell damage. Over the last two decades, there has been a surge in research revealing the basic molecular mechanisms of autophagy in mammalian cells. A corollary of an advanced understanding of autophagy has been a concurrent expansion of research into understanding autophagic function and dysfunction in pathology. Recent studies have revealed a pivotal role for autophagy in drug toxicity, and for utilizing autophagic components as diagnostic markers and therapeutic targets in treating disease and cancer. In this review, advances in understanding the molecular basis of mammalian autophagy, methods used to induce and evaluate autophagy, and the diverse interactions between autophagy and drug toxicity, disease progression and carcinogenesis are discussed. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Dayton M Petibone
- National Center for Toxicological Research, US FDA, Division of Genetic and Molecular Toxicology, Jefferson, AR, 72079, USA
| | - Waqar Majeed
- Center of Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, AR, 72204, USA
| | - Daniel A Casciano
- Center of Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, AR, 72204, USA
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50
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Kharaziha P, Chioureas D, Baltatzis G, Fonseca P, Rodriguez P, Gogvadze V, Lennartsson L, Björklund AC, Zhivotovsky B, Grandér D, Egevad L, Nilsson S, Panaretakis T. Sorafenib-induced defective autophagy promotes cell death by necroptosis. Oncotarget 2016; 6:37066-82. [PMID: 26416459 PMCID: PMC4741916 DOI: 10.18632/oncotarget.5797] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 08/29/2015] [Indexed: 01/06/2023] Open
Abstract
Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5−/− cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis.
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Affiliation(s)
- Pedram Kharaziha
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Dimitris Chioureas
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - George Baltatzis
- Department of Medicine, School of Health Sciences, University of Athens, Athens, Greece
| | - Pedro Fonseca
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Patricia Rodriguez
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Vladimir Gogvadze
- Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden
| | - Lena Lennartsson
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Ann-Charlotte Björklund
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden
| | - Dan Grandér
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Lars Egevad
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Sten Nilsson
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Theocharis Panaretakis
- Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden
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