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Wang M, Zhao JH, Tang MX, Li M, Zhao H, Li ZY, Liu AD. Cell Death Modalities in Therapy of Melanoma. Int J Mol Sci 2025; 26:3475. [PMID: 40331942 PMCID: PMC12026598 DOI: 10.3390/ijms26083475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 03/31/2025] [Accepted: 04/02/2025] [Indexed: 05/08/2025] Open
Abstract
Melanoma, one of the most lethal cancers, demands urgent and effective treatment strategies. However, a successful therapeutic approach requires a precise understanding of the mechanisms underlying melanoma initiation and progression. This review provides an overview of melanoma pathogenesis, identifies current pathogenic factors contributing to mortality, and explores targeted therapy and checkpoint inhibitor therapy. Furthermore, we examine melanoma classification and corresponding therapies, along with advancements in various cell death mechanisms for melanoma treatment. We also discuss the current treatment status along with some drawbacks encountered during research stages such as resistance and metastasis.
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Affiliation(s)
- Meng Wang
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.W.); (J.-H.Z.); (M.-X.T.); (M.L.); (H.Z.)
| | - Jia-Hui Zhao
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.W.); (J.-H.Z.); (M.-X.T.); (M.L.); (H.Z.)
| | - Ming-Xuan Tang
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.W.); (J.-H.Z.); (M.-X.T.); (M.L.); (H.Z.)
| | - Meng Li
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.W.); (J.-H.Z.); (M.-X.T.); (M.L.); (H.Z.)
| | - Hu Zhao
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.W.); (J.-H.Z.); (M.-X.T.); (M.L.); (H.Z.)
- National Demonstration Center for Experimental Basic Medical Education, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhong-Yu Li
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.W.); (J.-H.Z.); (M.-X.T.); (M.L.); (H.Z.)
- National Demonstration Center for Experimental Basic Medical Education, Huazhong University of Science and Technology, Wuhan 430030, China
| | - An-Dong Liu
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.W.); (J.-H.Z.); (M.-X.T.); (M.L.); (H.Z.)
- National Demonstration Center for Experimental Basic Medical Education, Huazhong University of Science and Technology, Wuhan 430030, China
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Abd-Elmagid WM, Amr KS, Ahmed HA, Ali D, Abdelhamed A. Autophagy and Premature Graying of Hair: The Role of LC3 as a Biomarker in a Case-Control Study. Dermatol Pract Concept 2025; 15:dpc.1502a4876. [PMID: 40401898 PMCID: PMC12090954 DOI: 10.5826/dpc.1502a4876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 05/23/2025] Open
Abstract
INTRODUCTION Premature graying of hair (PGH) is a common disorder with a multifactorial etiology. Autophagy, which is self-cellular digestion, has been linked to melanin pigment formation; however, the role of autophagy in PGH has not been investigated well. OBJECTIVES The study aimed to evaluate the relationship between PGH and autophagy by measuring gene expression and serum microtubule-associated protein light chain 3 (LC3) concentration. METHODS A case-control study was conducted on 39 PGH patients and 21 controls. Patients clinically diagnosed with PGH and aged <30 years were included in the study. Blood samples were taken to detect LC3B protein by ELISA in the serum of both groups. White hairs from both groups were collected to detect LC3B gene expression by PCR. RESULTS There was a statistically significant difference between the two groups as regards expression levels of the LC3 gene by PCR (P<0.001), with the mean in the control group (0.71± 0.3) lower than in the PGH group (5.1 ± 1.4). Also, there was a positive significant correlation between LC3 concentration and LC3 gene expression in control (r=0.867, P< 0.001) and in PGH patients (r=0.954, P≤0.001). Multivariate logistic regression analysis for PGH predictors using age, sex (female), hemoglobin level, LC3 concentration, and LC3 gene expression revealed that the only predictor of PGH was LC3 gene expression. CONCLUSIONS Premature graying of hair may have a link with autophagy. LC3 gene expression was increased in PGH patients as compared to the control. LC3 gene expression may be an independent predictor of PGH development. Autophagy modulation may be a therapeutic target for PGH.
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Affiliation(s)
- Wafaa Mohamed Abd-Elmagid
- Dermatology, Venereology and Andrology Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Khalda S. Amr
- Medical Molecular Genetics Department, Human Genetics & Genome Research Division (HGGR), National Research Centre (NRC), Egypt
| | - Hoda A. Ahmed
- Medical Molecular Genetics Department, Human Genetics & Genome Research Division (HGGR), National Research Centre (NRC), Egypt
| | - Dina Ali
- Dermatology, Venereology and Andrology Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Amr Abdelhamed
- Dermatology, Venereology and Andrology Department, Faculty of Medicine, Sohag University, Sohag, Egypt
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Zahoor A, Khazer R, Mehraj I, Gani U, Fayaz F, Khanday FA, Bhat SS. Aberrant DNA methylation as a key modulator of cell death pathways: insights into cancer progression and other diseases. Funct Integr Genomics 2025; 25:50. [PMID: 40024973 DOI: 10.1007/s10142-025-01552-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 03/04/2025]
Abstract
Cell death plays a significant role in the physiology of all living organisms, and its disruption is the underlying cause of various diseases. Previously, it was assumed that apoptosis and necrosis were the only means of cell death. Recent discoveries of alternative cell death pathways highlighted a complicated interplay between cell death regulation and its role in numerous human pathologies. DNA methylation is a universal epigenetic mechanism characterized by the covalent addition of a methyl group to cytosine in CpG dinucleotides. Alterations in DNA methylation patterns lead to the dysregulation of multiple cell death pathways. DNA methylome studies on cell death pathways have improved our understanding of the mechanism of various types of cell death, such as apoptosis, pyroptosis, necroptosis, ferroptosis, anoikis, autophagy, and cuproptosis. The irregular DNA methylation patterns of genes encoding proteins linked to multiple cell death pathways could underlie resistance to cell death. Dysregulation of cell death is linked to ailments in humans, such as cancer. However, unlike genetic alterations, DNA methylation is reversible, making it extremely interesting for therapeutics considering the potential use of DNA methyltransferase inhibitors. Furthermore, tumor microenvironment and genetic heterogeneity of cancers may influence the methylation-dependent regulation of cell death, contributing to tumor progression and therapeutic resistance. Understanding how DNA methylation influences cell death pathways may illuminate the underlying causes of cancer. This review explores the significance of the DNA methylation patterns of key genes involved in cell death pathways, emphasizing their connections and identifying potential gaps that could be exploited for developing epigenetic therapies targeting cancer.
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Affiliation(s)
- Ambreen Zahoor
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST-K, Srinagar, 190006, J&K, India
| | - Rafia Khazer
- Department of Biotechnology, University of Kashmir, Srinagar, 190006, J&K, India
| | - Insha Mehraj
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST-K, Srinagar, 190006, J&K, India
| | - Ubaid Gani
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST-K, Srinagar, 190006, J&K, India
| | - Falah Fayaz
- Govt. Medical College, Srinagar, 190001, J&K, India
| | - Firdous A Khanday
- Department of Biotechnology, University of Kashmir, Srinagar, 190006, J&K, India
| | - Sahar Saleem Bhat
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST-K, Srinagar, 190006, J&K, India.
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Zhai P, Sung EA, Shiheido-Watanabe Y, Takayama K, Tian Y, Sadoshima J. Suppression of autophagy induces senescence in the heart. J Mol Cell Cardiol 2024; 195:83-96. [PMID: 39117176 DOI: 10.1016/j.yjmcc.2024.08.001] [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: 03/25/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
Aging is a critical risk factor for heart disease, including ischemic heart disease and heart failure. Cellular senescence, characterized by DNA damage, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes. Senescence precipitates the aging process in surrounding cells and the organ through paracrine mechanisms. Generalized autophagy, which degrades cytosolic materials in a non-selective manner, is decreased during aging in the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Although suppression of generalized autophagy could promote senescence, it remains unclear whether the suppression of autophagy directly stimulates senescence in cardiomyocytes, which, in turn, promotes myocardial dysfunction in the heart. We addressed this question using mouse models with a loss of autophagy function. Suppression of general autophagy in cardiac-specific Atg7 knockout (Atg7cKO) mice caused accumulation of senescent cardiomyocytes. Induction of senescence via downregulation of Atg7 was also observed in chimeric Atg7 cardiac-specific KO mice and cultured cardiomyocytes in vitro, suggesting that the effect of autophagy suppression upon induction of senescence is cell autonomous. ABT-263, a senolytic agent, reduced the number of senescent myocytes and improved cardiac function in Atg7cKO mice. Suppression of autophagy and induction of senescence were also observed in doxorubicin-treated hearts, where reactivation of autophagy alleviated senescence in cardiomyocytes and cardiac dysfunction. These results suggest that suppression of general autophagy directly induces senescence in cardiomyocytes, which in turn promotes cardiac dysfunction.
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Affiliation(s)
- Peiyong Zhai
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Eun-Ah Sung
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Yuka Shiheido-Watanabe
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Koichiro Takayama
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Yimin Tian
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103.
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Ali ML, Roky AH, Azad SAK, Shaikat AH, Meem JN, Hoque E, Ahasan AMF, Islam MM, Arif MSR, Mostaq MS, Mahmud MZ, Amin MN, Mahmud MA. Autophagy as a targeted therapeutic approach for skin cancer: Evaluating natural and synthetic molecular interventions. CANCER PATHOGENESIS AND THERAPY 2024; 2:231-245. [PMID: 39371094 PMCID: PMC11447340 DOI: 10.1016/j.cpt.2024.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/22/2024] [Accepted: 01/28/2024] [Indexed: 10/08/2024]
Abstract
Skin cancer, a prevalent malignancy worldwide, poses significant health concerns owing to its increasing incidence. Autophagy, a natural cellular process, is a pivotal event in skin cancer and has advantageous and detrimental effects. This duality has prompted extensive investigations into medical interventions targeting autophagy modulation for their substantial therapeutic potential. This systematic review aimed to investigate the relationship between skin cancer and autophagy and the contribution and mechanism of autophagy modulators in skin cancer. We outlined the effectiveness and safety of targeting autophagy as a promising therapeutic strategy for the treatment of skin cancer. This comprehensive review identified a diverse array of autophagy modulators with promising potential for the treatment of skin cancer. Each of these compounds demonstrates efficacy through distinct physiological mechanisms that have been elucidated in detail. Interestingly, findings from a literature search indicated that none of the natural, synthetic, or semisynthetic compounds exhibited notable adverse effects in either human or animal models. Consequently, this review offers novel mechanistic and therapeutic perspectives on the targeted modulation of autophagy in skin cancer.
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Affiliation(s)
- Md. Liakot Ali
- Department of Pharmacy, University of Chittagong, Chattogram 4331, Bangladesh
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
| | - Amdad Hossain Roky
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
- Department of Pharmacy, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - S.M. Asadul Karim Azad
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
- Department of Pharmacy, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - Abdul Halim Shaikat
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
- Department of Pharmacy, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - Jannatul Naima Meem
- Department of Pharmacy, University of Chittagong, Chattogram 4331, Bangladesh
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
| | - Emtiajul Hoque
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
- Department of Pharmacy, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - Abu Mohammed Fuad Ahasan
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
- Department of Pharmacy, International Islamic University Chittagong, Chattogram 4318, Bangladesh
| | - Mohammed Murshedul Islam
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
- Department of Pharmacy, Daffodil International University, Dhaka 1216, Bangladesh
| | - Md. Saifur Rahaman Arif
- Pratyasha Health Biomedical Research Center, Dhaka 1230, Bangladesh
- Department of Pharmacy, BGC Trust University Bangladesh, Chattogram 4381, Bangladesh
| | - Md. Saqline Mostaq
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
| | | | - Mohammad Nurul Amin
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
| | - Md. Ashiq Mahmud
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
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Pangilinan C, Klionsky DJ, Liang C. Emerging dimensions of autophagy in melanoma. Autophagy 2024; 20:1700-1711. [PMID: 38497492 PMCID: PMC11262229 DOI: 10.1080/15548627.2024.2330261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 02/27/2024] [Accepted: 03/10/2024] [Indexed: 03/19/2024] Open
Abstract
Macroautophagy/autophagy has previously been regarded as simply a way for cells to deal with nutrient emergency. But explosive work in the last 15 years has given increasingly new knowledge to our understanding of this process. Many of the functions of autophagy that are unveiled from recent studies, however, cannot be reconciled with this conventional view of cell survival but, instead, point to autophagy being integrally involved at a deeper level of cell biology, playing a critical role in maintaining homeostasis and promoting an integrated stress/immune response. The new appreciation of the role of autophagy in the evolutionary trajectory of cancer and cancer interaction with the immune system provides a mechanistic framework for understanding the clinical benefits of autophagy-based therapies. Here, we examine current knowledge of the mechanisms and functions of autophagy in highly plastic and aggressive melanoma as a model disease of human malignancy, while highlighting emerging dimensions indicating that autophagy is at play beyond its classical face.Abbreviation: AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; ATG: autophagy related; BRAF: B-Raf proto-oncogene, serine/threonine kinase; CAFs: cancer-associated fibroblasts; CCL5: C-C motif chemokine ligand 5; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTLA4: cytotoxic T-lymphocyte associated protein 4; CTL: cytotoxic T lymphocyte; DAMPs: danger/damage-associated molecular patterns; EGFR: epidermal growth factor receptor; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; FITM2: fat storage inducing transmembrane protein 2; HCQ: hydroxychloroquine; ICB: immune checkpoint blockade; ICD: immunogenic cell death; LDH: lactate dehydrogenase; MAPK: mitogen-activated protein kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NDP52: nuclear dot protein 52; NFKB/NF-κ B: nuclear factor kappa B; NBR1: the neighbor of BRCA1; NK: natural killer; NRF1: nuclear respiratory factor 1; NSCLC: non-small-cell lung cancer; OPTN: optineurin; PDAC: pancreatic ductal adenocarcinoma; PDCD1/PD-1: programmed cell death 1; PPT1: palmitoyl-protein thioesterase 1; PTEN: phosphatase and tensin homolog; PTK2/FAK1: protein tyrosine kinase 2; RAS: rat sarcoma; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TAX1BP1: Tax1 binding protein 1; TFEB: transcription factor EB; TGFB/TGF-β: transforming growth factor beta; TMB: tumor mutational burden; TME: tumor microenvironment; TSC1: TSC complex subunit 1; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated.
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Affiliation(s)
- Christian Pangilinan
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
| | | | - Chengyu Liang
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
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Liu HS, Wang YP, Lin PW, Chu ML, Lan SH, Wu SY, Lee YR, Chang HY. The role of Atg5 gene in tumorigenesis under autophagy deficiency conditions. Kaohsiung J Med Sci 2024; 40:631-641. [PMID: 38826147 DOI: 10.1002/kjm2.12853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 06/04/2024] Open
Abstract
Autophagy is a self-recycling machinery to maintain cellular homeostasis by degrading harmful materials in the cell. Autophagy-related gene 5 (Atg5) is required for autophagosome maturation. However, the role of Atg5 in tumorigenesis under autophagy deficient conditions remains unclear. This study focused on the autophagy-independent role of Atg5 and the underlying mechanism in tumorigenesis. We demonstrated that knockout of autophagy-related genes including Atg5, Atg7, Atg9, and p62 in mouse embryonic fibroblast (MEF) cells consistently decreased cell proliferation and motility, implying that autophagy is required to maintain diverse cellular functions. An Atg7 knockout MEF (Atg7-/- MEF) cell line representing deprivation of autophagy function was used to clarify the role of Atg5 transgene in tumorigenesis. We found that Atg5-overexpressed Atg7-/-MEF (clone A) showed increased cell proliferation, colony formation, and migration under autophagy deficient conditions. Accordingly, rescuing the autophagy deficiency of clone A by overexpression of Atg7 gene shifts the role of Atg5 from pro-tumor to anti-tumor status, indicating the dual role of Atg5 in tumorigenesis. Notably, the xenograft mouse model showed that clone A of Atg5-overexpressed Atg7-/- MEF cells induced temporal tumor formation, but could not prolong further tumor growth. Finally, biomechanical analysis disclosed increased Wnt5a secretion and p-JNK expression along with decreased β-catenin expression. In summary, Atg5 functions as a tumor suppressor to protect the cell under normal conditions. In contrast, Atg5 shifts to a pro-tumor status under autophagy deprivation conditions.
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Affiliation(s)
- Hsiao-Sheng Liu
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Tropical Medicine College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Teaching and Research Center, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medial University, Kaohsiung, Taiwan
| | - Yin-Ping Wang
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Wen Lin
- Tropical Medicine College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Man-Ling Chu
- Tropical Medicine College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - 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
| | - 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
| | - Ying-Ray Lee
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hong-Yi Chang
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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Liang W, Zhao Y, Cai B, Huang Y, Chen X, Ni N, Wang Y, Lin Z, Lin C, Huang K. Psychological stress induces hair regenerative disorders through corticotropin-releasing hormone-mediated autophagy inhibition. Biochem Biophys Res Commun 2024; 699:149564. [PMID: 38277725 DOI: 10.1016/j.bbrc.2024.149564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/09/2024] [Accepted: 01/22/2024] [Indexed: 01/28/2024]
Abstract
Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss.
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Affiliation(s)
- Wenzi Liang
- Shantou University Mental Health Center, Shantou University Medical College, Shantou, PR China
| | - Yinglin Zhao
- Shantou University Mental Health Center, Shantou University Medical College, Shantou, PR China
| | - Bozhi Cai
- Molecular Cardiology Laboratory, First Affiliated Hospital of Shantou University Medical College, Shantou, PR China
| | - Yuxin Huang
- Department of Histology and Embryology, Shantou University Medical College, Shantou, PR China
| | - Xiuwen Chen
- Department of Neurology, First Affiliated Hospital of Shantou University Medical College, Shantou, PR China
| | - Na Ni
- Shantou University Medical College, Shantou, PR China
| | - Yingshan Wang
- Shantou University Medical College, Shantou, PR China
| | - Zhaoping Lin
- Shantou University Medical College, Shantou, PR China
| | - Changmin Lin
- Department of Histology and Embryology, Shantou University Medical College, Shantou, PR China.
| | - Keng Huang
- Emergency Department, Second Affiliated Hospital of Shantou University Medical College, Shantou, PR China.
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Han W, Wang W, Wang Q, Maduray K, Hao L, Zhong J. A review on regulation of DNA methylation during post-myocardial infarction. Front Pharmacol 2024; 15:1267585. [PMID: 38414735 PMCID: PMC10896928 DOI: 10.3389/fphar.2024.1267585] [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: 07/26/2023] [Accepted: 01/25/2024] [Indexed: 02/29/2024] Open
Abstract
Myocardial infarction (MI) imposes a huge medical and economic burden on society, and cardiac repair after MI involves a complex series of processes. Understanding the key mechanisms (such as apoptosis, autophagy, inflammation, and fibrosis) will facilitate further drug development and patient treatment. Presently, a substantial body of evidence suggests that the regulation of epigenetic processes contributes to cardiac repair following MI, with DNA methylation being among the notable epigenetic factors involved. This article will review the research on the mechanism of DNA methylation regulation after MI to provide some insights for future research and development of related drugs.
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Affiliation(s)
- Wenqiang Han
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Wenxin Wang
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Qinhong Wang
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Kellina Maduray
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Li Hao
- Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jingquan Zhong
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
- Department of Cardiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
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10
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He B, Liang J, Qin Q, Zhang Y, Shi S, Cao J, Zhang Z, Bie Q, Zhao R, Wei L, Zhang B, Zhang B. IL-13/IL-13RA2 signaling promotes colorectal cancer stem cell tumorigenesis by inducing ubiquitinated degradation of p53. Genes Dis 2024; 11:495-508. [PMID: 37588218 PMCID: PMC10425805 DOI: 10.1016/j.gendis.2023.01.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/03/2023] [Accepted: 01/17/2023] [Indexed: 08/18/2023] Open
Abstract
Cancer stem cells (CSCs) are considered tumor-initiating cells and the main drivers of disease progression. Targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the up-regulation of IL-13RA2 expression in colorectal cancer (CRC) tissues and spheroid cells. The expression of IL-13RA2 was positively correlated with canonical stemness markers in CRC. We further demonstrated that the level of IL-13 was up-regulated in the serum of CRC patients. Biologically, recombinant IL-13 (rIL-13) stimulation promoted the sphere formation, proliferation, and migration of CRC cells in vitro and enhanced tumorigenesis in vivo. This phenotype could be reversed by knocking down IL-13RA2. Mechanistically, IL-13 activated autophagy by inducing LC3I/LC3II transformation in CRC-CSCs, which was crucial for the biological functions of IL-13. We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein, enhancing the interaction of UBE3C and p53, thereby inducing the K48-linked ubiquitination of p53. In conclusion, the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination, adding an important layer to the connection between IL-13 and p53, which can be translated into novel targeted therapies.
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Affiliation(s)
- Baoyu He
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
- Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Jing Liang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Qianqian Qin
- Department of Reproductive Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Yuqin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Shuo Shi
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Jinghe Cao
- Department of Reproductive Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Zhixin Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Qingli Bie
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
- Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Rou Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Li Wei
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Baogui Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China
- Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining, Shandong 272067, China
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11
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Wang Y, Fu Y, Lu Y, Chen S, Zhang J, Liu B, Yuan Y. Unravelling the complexity of lncRNAs in autophagy to improve potential cancer therapy. Biochim Biophys Acta Rev Cancer 2023; 1878:188932. [PMID: 37329993 DOI: 10.1016/j.bbcan.2023.188932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/30/2023] [Accepted: 06/10/2023] [Indexed: 06/19/2023]
Abstract
Autophagy is well-known as an internal catabolic process that is evolutionarily conserved and performs the key biological function in maintaining cellular homeostasis. It is tightly controlled by several autophagy-related (ATG) proteins, which are closely associated with many types of human cancers. However, what has remained controversial is the janus roles of autophagy in cancer progression. Interestingly, the biological function of long non-coding RNAs (lncRNAs) in autophagy has been gradually understood in different types of human cancers. More recently, numerous studies have demonstrated that several lncRNAs may regulate some ATG proteins and autophagy-related signaling pathways to either activate or inhibit the autophagic process in cancer. Thus, in this review, we summarize the latest advance in the knowledge of the complicated relationships between lncRNAs and autophagy in cancer. Also, the in-depth dissection of the lncRNAs-autophagy-cancers axis involved in this review would shed new light on discovery of more potential cancer biomarkers and therapeutic targets in the future.
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Affiliation(s)
- Yi Wang
- Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuqi Fu
- Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yingying Lu
- Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Siwei Chen
- Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jin Zhang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China.
| | - Bo Liu
- Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Yong Yuan
- Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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12
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Maharati A, Samsami Y, Latifi H, Tolue Ghasaban F, Moghbeli M. Role of the long non-coding RNAs in regulation of Gemcitabine response in tumor cells. Cancer Cell Int 2023; 23:168. [PMID: 37580768 PMCID: PMC10426205 DOI: 10.1186/s12935-023-03004-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/26/2023] [Indexed: 08/16/2023] Open
Abstract
Chemotherapy is widely used as one of the first line therapeutic methods in cancer patients. However, chemotherapeutic resistance is one of the most common problems in cancer patients, which leads to the therapeutic failure and tumor relapse. Considering the side effects of chemotherapy drugs in normal tissues, it is required to investigate the molecular mechanisms involved in drug resistance to improve the therapeutic strategies in cancer patients. Long non-coding RNAs (lncRNAs) have pivotal roles in regulation of cellular processes associated with drug resistance. LncRNAs deregulations have been frequently reported in a wide range of chemo-resistant tumors. Gemcitabine (GEM) as a nucleoside analog has a wide therapeutic application in different cancers. However, GEM resistance is considered as a therapeutic challenge. Considering the role of lncRNAs in the occurrence of GEM resistance, in the present review we discussed the molecular mechanisms of lncRNAs in regulation of GEM response among cancer patients. It has been reported that lncRNAs have mainly an oncogenic role as the inducers of GEM resistance through direct or indirect regulation of transcription factors, autophagy, polycomb complex, and signaling pathways such as PI3K/AKT, MAPK, WNT, JAK/STAT, and TGF-β. This review paves the way to present the lncRNAs as non-invasive markers to predict GEM response in cancer patients. Therefore, lncRNAs can be introduced as the efficient markers to reduce the possible chemotherapeutic side effects in GEM resistant cancer patients and define a suitable therapeutic strategy among these patients.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yalda Samsami
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Latifi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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13
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Fratta E, Giurato G, Guerrieri R, Colizzi F, Dal Col J, Weisz A, Steffan A, Montico B. Autophagy in BRAF-mutant cutaneous melanoma: recent advances and therapeutic perspective. Cell Death Discov 2023; 9:202. [PMID: 37386023 DOI: 10.1038/s41420-023-01496-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 06/06/2023] [Accepted: 06/16/2023] [Indexed: 07/01/2023] Open
Abstract
Macroautophagy, hereafter referred to as autophagy, represents a highly conserved catabolic process that maintains cellular homeostasis. At present, the role of autophagy in cutaneous melanoma (CM) is still controversial, since it appears to be tumor-suppressive at early stages of malignant transformation and cancer-promoting during disease progression. Interestingly, autophagy has been found to be often increased in CM harboring BRAF mutation and to impair the response to targeted therapy. In addition to autophagy, numerous studies have recently conducted in cancer to elucidate the molecular mechanisms of mitophagy, a selective form of mitochondria autophagy, and secretory autophagy, a process that facilitates unconventional cellular secretion. Although several aspects of mitophagy and secretory autophagy have been investigated in depth, their involvement in BRAF-mutant CM biology has only recently emerged. In this review, we aim to overview autophagy dysregulation in BRAF-mutant CM, along with the therapeutic advantages that may arise from combining autophagy inhibitors with targeted therapy. In addition, the recent advances on mitophagy and secretory autophagy involvement in BRAF-mutant CM will be also discussed. Finally, since a number of autophagy-related non-coding RNAs (ncRNAs) have been identified so far, we will briefly discussed recent advances linking ncRNAs to autophagy regulation in BRAF-mutant CM.
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Affiliation(s)
- Elisabetta Fratta
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
- Genome Research Center for Health - CRGS, 84081, Baronissi, SA, Italy
| | - Roberto Guerrieri
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Francesca Colizzi
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Jessica Dal Col
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
- Genome Research Center for Health - CRGS, 84081, Baronissi, SA, Italy
- Molecular Pathology and Medical Genomics Program, AOU 'S. Giovanni di Dio e Ruggi d'Aragona' University of Salerno and Rete Oncologica Campana, 84131, Salerno, Italy
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Barbara Montico
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
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14
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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: 23] [Impact Index Per Article: 11.5] [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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15
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Metur SP, Lei Y, Zhang Z, Klionsky DJ. Regulation of autophagy gene expression and its implications in cancer. J Cell Sci 2023; 136:jcs260631. [PMID: 37199330 PMCID: PMC10214848 DOI: 10.1242/jcs.260631] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023] Open
Abstract
Autophagy is a catabolic cellular process that targets and eliminates superfluous cytoplasmic components via lysosomal degradation. This evolutionarily conserved process is tightly regulated at multiple levels as it is critical for the maintenance of homeostasis. Research in the past decade has established that dysregulation of autophagy plays a major role in various diseases, such as cancer and neurodegeneration. However, modulation of autophagy as a therapeutic strategy requires identification of key players that can fine tune the induction of autophagy without complete abrogation. In this Review, we summarize the recent discoveries on the mechanism of regulation of ATG (autophagy related) gene expression at the level of transcription, post transcription and translation. Furthermore, we briefly discuss the role of aberrant expression of ATG genes in the context of cancer.
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Affiliation(s)
- Shree Padma Metur
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yuchen Lei
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Zhihai Zhang
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
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16
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Zhang S, Qian Y, Ye L. Delineating the twin role of autophagy in lung cancer. Biol Futur 2023:10.1007/s42977-023-00165-4. [PMID: 37120768 DOI: 10.1007/s42977-023-00165-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 03/26/2023] [Indexed: 05/01/2023]
Abstract
Autophagy represents an intracellular defense mechanism equipped within each eukaryotic cells to enable them to cope with variety of physical, chemical, and biological stresses. This mechanism helps to restore the homeostasis and preserve the cellular integrity and function of the cells. In these conditions, such as hypoxia, nutrient deprivation, inhibition of protein synthesis or microbial attack, the process of autophagy is upregulated to maintain cellular homeostasis. The role of autophagy in cancer is an intriguing topic which needs further exploration. This process of autophagy has been many times referred as a double-edged sword in the process of tumorigenesis. In the initial stages, it may act as a tumor suppressor and enable to quench the damaged organelles and harmful molecules generated. In more advanced stages, autophagy has been shown to act as a tumor-promoting system as it may help the cancer cells to cope better with stressful microenvironments. Besides this, autophagy has been associated with development of resistance to anticancer drugs as well as promoting the immune evasion in cancer cells, representing a serious obstacle in cancer treatment and its outcome. Also, autophagy is associated with hallmarks of cancer that may lead to activation of invasion and metastasis. The information on this twin role needs further exploration and deeper understanding of the pathways involved. In this review, we discuss the various aspects of autophagy during tumor development, from early to late stages of tumor growth. Both the protective role of autophagy in preventing tumor growth and the underlying mechanisms adopted with evidence from past studies have been detailed. Further, the role of autophagy in conferring resistance to distinct lung cancer treatment and immune shielding properties has also been discussed. This is essential for further improving on treatment outcome and success rates.
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Affiliation(s)
- Shaoqin Zhang
- Department of Chest Surgery, Shengzhou People's Hospital (The First Affiliated Hospital of Zhejiang University Shengzhou Branch), Shaoxing, 312400, Zhejiang, China
| | - Ye Qian
- Department of Oncology, Hai 'an Hospital Affiliated to Nantong University, Haian, 226600, Jiangsu, China
| | - Luhai Ye
- Department of Chest Surgery, Xinchang Country Hospital of TCM, Shaoxing, 312500, Zhejiang, China.
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17
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Tyagi A, Chandrasekaran B, Navin AK, Shukla V, Baby BV, Ankem MK, Damodaran C. Molecular interplay between NOX1 and autophagy in cadmium-induced prostate carcinogenesis. Free Radic Biol Med 2023; 199:44-55. [PMID: 36764624 DOI: 10.1016/j.freeradbiomed.2023.02.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/18/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023]
Abstract
Chronic exposure to cadmium (Cd), a class I carcinogen, leads to malignant transformation of normal prostate epithelial cells (RWPE-1). The constant generation of Cd-induced ROS and resulting ER stress induces cellular responses that are needed for cell survival, and autophagy has an important role in this process. However, the mechanisms that regulate Cd-induced ROS and how these differ in terms of acute and chronic cadmium exposure remain unexplained. Here, we show that acute or chronic Cd exposure facilitates NOX1 assembly by activating its cytosolic regulators p47phox and p67phox in RWPE-1 cells. Upregulation of NOX1 complex proteins and generation of ROS activates unfolded protein response (UPR) via phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2α), and selective translation of activating transcription factor 4 (ATF4). Chronic Cd exposure constantly activates NOX1 complex and generates consistent ROS and ER stress that led to defective autophagy, wherein ATG5 expression is downregulated in contrast to acute Cd exposure. As a result, selective/defective autophagy creates depletion of autophagosome-lysosome fusion that gives a survival advantage to transforming cells, which is not available to RWPE-1 cells acutely exposed to Cd. Knockdown of key molecules in a lockstep manner directly affects the most downstream autophagy pathways in transforming cells. Overall, this study demonstrates that assembly of NOX1 complex proteins is indispensable for Cd-induced persistent ROS and controls ER stress-induced defective autophagy in mice and humans.
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Affiliation(s)
- Ashish Tyagi
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX, 77845, USA
| | - Balaji Chandrasekaran
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX, 77845, USA
| | - Ajit K Navin
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX, 77845, USA
| | - Vaibhav Shukla
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX, 77845, USA
| | - Becaa V Baby
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Murali K Ankem
- Department of Urology, University of Louisville, Louisville, KY, USA
| | - Chendil Damodaran
- Department of Pharmacology, College of Pharmacy, Texas A&M University, College Station, TX, 77845, USA; Department of Urology, University of Louisville, Louisville, KY, USA.
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18
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Pangilinan C, Xu X, Herlyn M, Liang C. Autophagy Paradox: Strategizing Treatment Modality in Melanoma. Curr Treat Options Oncol 2023; 24:130-145. [PMID: 36670319 PMCID: PMC9883356 DOI: 10.1007/s11864-023-01053-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2022] [Indexed: 01/22/2023]
Abstract
OPINION STATEMENT The primordial autophagy process, originally identified as a starvation response in baker's yeast, has since been shown to have a wide spectrum of functions other than survival. In many cases, it is accepted that autophagy operates as a key tumor suppressor mechanism that protects cells from adverse environmental cues by enforcing homeostasis and maintaining the functional and structural integrity of organelles. Paradoxically, heightened states of autophagy are also seen in some cancers, leading to the prevailing view that the pro-survival aspect of autophagy might be hijacked by some tumors to promote their fitness and pathogenesis. Notably, recent studies have revealed a broad range of cell-autonomous autophagy in reshaping tumor microenvironment and maintaining lineage integrity and immune homeostasis, calling for a renewed understanding of autophagy beyond its classical roles in cell survival. Here, we evaluate the increasing body of literature that argues the "double-edged" consequences of autophagy manipulation in cancer therapy, with a particular focus on highly plastic and mutagenic melanoma. We also discuss the caveats that must be considered when evaluating whether autophagy blockade is the effector mechanism of some anti-cancer therapy particularly associated with lysosomotropic agents. If autophagy proteins are to be properly exploited as targets for anticancer drugs, their diverse and complex roles should also be considered.
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Affiliation(s)
- Christian Pangilinan
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA
| | - Chengyu Liang
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
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19
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López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab 2023; 35:12-35. [PMID: 36599298 DOI: 10.1016/j.cmet.2022.11.001] [Citation(s) in RCA: 230] [Impact Index Per Article: 115.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/11/2022] [Accepted: 11/07/2022] [Indexed: 01/05/2023]
Abstract
Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.
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Affiliation(s)
- Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - David Roiz-Valle
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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20
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Al-Odat OS, Guirguis DA, Schmalbach NK, Yao G, Budak-Alpdogan T, Jonnalagadda SC, Pandey MK. Autophagy and Apoptosis: Current Challenges of Treatment and Drug Resistance in Multiple Myeloma. Int J Mol Sci 2022; 24:ijms24010644. [PMID: 36614089 PMCID: PMC9820338 DOI: 10.3390/ijms24010644] [Citation(s) in RCA: 15] [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: 11/30/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
Over the past two decades, the natural history of multiple myeloma (MM) has evolved dramatically, owing primarily to novel agents targeting MM in the bone marrow microenvironment (BMM) pathways. However, the mechanisms of resistance acquisition remain a mystery and are poorly understood. Autophagy and apoptosis are tightly controlled processes and play a critical role in the cell growth, development, and survival of MM. Genetic instability and abnormalities are two hallmarks of MM. During MM progression, plasma malignant cells become genetically unstable and activate various signaling pathways, resulting in the overexpression of abnormal proteins that disrupt autophagy and apoptosis biological processes. Thus, achieving a better understanding of the autophagy and apoptosis processes and the proteins that crosslinked both pathways, could provide new insights for the MM treatment and improve the development of novel therapeutic strategies to overcome resistance. This review presents a sufficient overview of the roles of autophagy and apoptosis and how they crosslink and control MM progression and drug resistance. Potential combination targeting of both pathways for improving outcomes in MM patients also has been addressed.
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Affiliation(s)
- Omar S. Al-Odat
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, USA
| | - Daniel A. Guirguis
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Nicole K. Schmalbach
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Gabriella Yao
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | | | | | - Manoj K. Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- Correspondence: ; Tel.: +1-856-956-2751
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21
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Luo M, Ye L, Chang R, Ye Y, Zhang Z, Liu C, Li S, Jing Y, Ruan H, Zhang G, He Y, Liu Y, Xue Y, Chen X, Guo AY, Liu H, Han L. Multi-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy. Nat Commun 2022; 13:6345. [PMID: 36289218 PMCID: PMC9606020 DOI: 10.1038/s41467-022-33946-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 10/07/2022] [Indexed: 02/08/2023] Open
Abstract
Autophagy is a major contributor to anti-cancer therapy resistance. Many efforts have been made to understand and overcome autophagy-mediated therapy resistance, but these efforts have been unsuccessful in clinical applications. In this study, we establish an autophagy signature to estimate tumor autophagy status. We then classify approximately 10,000 tumor samples across 33 cancer types from The Cancer Genome Atlas into autophagy score-high and autophagy score-low groups. We characterize the associations between multi-dimensional molecular features and tumor autophagy, and further analyse the effects of autophagy status on drug response. In contrast to the conventional view that the induction of autophagy serves as a key resistance mechanism during cancer therapy, our analysis reveals that autophagy induction may also sensitize cancer cells to anti-cancer drugs. We further experimentally validate this phenomenon for several anti-cancer drugs in vitro and in vivo, and reveal that autophagy inducers potentially sensitizes tumor cells to etoposide through downregulating the expression level of DDIT4. Our study provides a comprehensive landscape of molecular alterations associated with tumor autophagy and highlights an opportunity to leverage multi-omics analysis to utilize multiple drug sensitivity induced by autophagy.
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Affiliation(s)
- Mei Luo
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Lin Ye
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruimin Chang
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Youqiong Ye
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhao Zhang
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Chunjie Liu
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Shengli Li
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Ying Jing
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Hang Ruan
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Guanxiong Zhang
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yi He
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yaoming Liu
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Yu Xue
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Xiang Chen
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - An-Yuan Guo
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
| | - Hong Liu
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Leng Han
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
- Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, USA.
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22
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L'Hôte V, Mann C, Thuret JY. From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biol 2022; 12:220171. [PMID: 36128715 PMCID: PMC9490338 DOI: 10.1098/rsob.220171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Senescence is a cellular stress response that involves prolonged cell survival, a quasi-irreversible proliferative arrest and a modification of the transcriptome that sometimes includes inflammatory gene expression. Senescent cells are resistant to apoptosis, and if not eliminated by the immune system they may accumulate and lead to chronic inflammation and tissue dysfunction. Senolytics are drugs that selectively induce cell death in senescent cells, but not in proliferative or quiescent cells, and they have proved a viable therapeutic approach in multiple mouse models of pathologies in which senescence is implicated. As the catalogue of senolytic compounds is expanding, novel survival strategies of senescent cells are uncovered, and variations in sensitivity to senolysis between different types of senescent cells emerge. We propose herein a mechanistic classification of senolytic drugs, based on the level at which they target senescent cells: directly disrupting BH3 protein networks that are reorganized upon senescence induction; downregulating survival-associated pathways essential to senescent cells; or modulating homeostatic processes whose regulation is challenged in senescence. With this approach, we highlight the important diversity of senescent cells in terms of physiology and pathways of apoptosis suppression, and we describe possible avenues for the development of more selective senolytics.
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Affiliation(s)
- Valentin L'Hôte
- CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette cedex, France
| | - Carl Mann
- CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette cedex, France
| | - Jean-Yves Thuret
- CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette cedex, France
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23
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Sun N, Tian Y, Chen Y, Guo W, Li C. Metabolic rewiring directs melanoma immunology. Front Immunol 2022; 13:909580. [PMID: 36003368 PMCID: PMC9393691 DOI: 10.3389/fimmu.2022.909580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/13/2022] [Indexed: 11/22/2022] Open
Abstract
Melanoma results from the malignant transformation of melanocytes and accounts for the most lethal type of skin cancers. In the pathogenesis of melanoma, disordered metabolism is a hallmark characteristic with multiple metabolic paradigms involved in, e.g., glycolysis, lipid metabolism, amino acid metabolism, oxidative phosphorylation, and autophagy. Under the driving forces of oncogenic mutations, melanoma metabolism is rewired to provide not only building bricks for macromolecule synthesis and sufficient energy for rapid proliferation and metastasis but also various metabolic intermediates for signal pathway transduction. Of note, metabolic alterations in tumor orchestrate tumor immunology by affecting the functions of surrounding immune cells, thereby interfering with their antitumor capacity, in addition to the direct influence on tumor cell intrinsic biological activities. In this review, we first introduced the epidemiology, clinical characteristics, and treatment proceedings of melanoma. Then, the components of the tumor microenvironment, especially different populations of immune cells and their roles in antitumor immunity, were reviewed. Sequentially, how metabolic rewiring contributes to tumor cell malignant behaviors in melanoma pathogenesis was discussed. Following this, the proceedings of metabolism- and metabolic intermediate-regulated tumor immunology were comprehensively dissertated. Finally, we summarized currently available drugs that can be employed to target metabolism to intervene tumor immunology and modulate immunotherapy.
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Affiliation(s)
- Ningyue Sun
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- School of Basic Medical Sciences, Fourth Military Medical University, Xi’an, China
| | - Yangzi Tian
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yuhan Chen
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- School of Basic Medical Sciences, Fourth Military Medical University, Xi’an, China
| | - Weinan Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- *Correspondence: Chunying Li, ; Weinan Guo,
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- *Correspondence: Chunying Li, ; Weinan Guo,
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24
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Li T, Zhou L, Fan M, Chen Z, Yan L, Lu H, Jia M, Wu H, Shan L. Human Umbilical Cord-Derived Mesenchymal Stem Cells Ameliorate Skin Aging of Nude Mice Through Autophagy-Mediated Anti-Senescent Mechanism. Stem Cell Rev Rep 2022; 18:2088-2103. [PMID: 35864432 DOI: 10.1007/s12015-022-10418-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2022] [Indexed: 10/17/2022]
Abstract
Skin aging is a currently irreversible process, affected by increased oxidative stress, activated cellular senescence, and lacked regeneration of the dermal layer. Mesenchymal stem cells (MSCs), such as human umbilical cord-derived MSCs (hucMSCs), have pro-regeneration and anti-aging potencies. To explore whether hucMSCs can be used to treat skin aging, this study employed skin-aging model of nude mice to conduct in vivo assays, including biochemical analysis of superoxide dismutase (SOD) and malondialdehyde (MDA), gross observation, histopathological observation, and immunohistochemical analysis. To clarify how hucMSCs work on skin aging, this study employed skin-aging model of human dermal fibroblasts (HDFs) to conduct in vitro assays by applying conditional medium of hucMSCs (CMM), including wound healing assay, senescence staining, flow cytometric oxidative detection, real time PCR, and western blot analysis. The in vivo data demonstrated that hucMSCs dose-dependently removed wrinkles, smoothed skin texture, and increased dermal thickness and collagen production of aged skin by reversing SOD and MDA levels and up-regulating Col-1 and VEGF expressions, indicating anti-oxidative and pro-regenerative effects against skin aging. The in vitro data revealed that hucMSCs significantly reversed the senescence of HDFs by promoting cell migration, inhibiting ROS production, and restoring the overexpressions of oxidative and senescent markers through paracrine mode of action, and the paracrine mechanism was mediated by the inhibition of autophagy. This study provided novel knowledge regarding the anti-aging efficacy and paracrine mechanism of hucMSCs on skin, making hucMSCs-based therapy a promising regime for skin aging treatment.
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Affiliation(s)
- Ting Li
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Department of Plastic and Aesthetic Center, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Li Zhou
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mengqiang Fan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zuxiang Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Li Yan
- Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd), Hangzhou, China
| | - Haishan Lu
- Department of Dermatology, PLA 903 Hospital, Hangzhou, China
| | - Ming Jia
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huiling Wu
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. .,Department of Plastic and Aesthetic Center, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
| | - Letian Shan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China. .,Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd), Hangzhou, China.
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25
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Taskaeva I, Gogaeva I, Shatruk A, Bgatova N. Lithium Enhances Autophagy and Cell Death in Skin Melanoma: An Ultrastructural and Immunohistochemical Study. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2022; 28:1-9. [PMID: 35592888 DOI: 10.1017/s1431927622000745] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Lithium is an inhibitor of glycogen synthase kinase 3 beta, which is traditionally used in the treatment of bipolar disorders and has antitumor effects. The aim of the current study was to determine if lithium salt causes autophagy and apoptosis in skin melanoma cells to enhance cell death. Light microscopy, transmission electron microscopy, immunohistochemistry, and immunofluorescence were used to study the mechanism of action of lithium carbonate in B16 melanoma cells in vivo. Proliferating cell nuclear antigen immunofluorescence assay revealed that the proliferation of B16 melanoma cells was suppressed by lithium treatment for 7 days. Electron microscopy demonstrated a significant increase in the number of autophagic vacuoles in lithium-treated cells relative to control. In addition, levels of autophagy markers LC3 beta and LAMP1 found in lithium-treated tumor xenografts were higher than levels of these markers in the control tumors. Lithium induced caspase-3 expression and apoptotic cell death in tumor cells. Thus, lithium carbonate is the compound that inhibits cell proliferation and stimulates cell death in melanoma cells through induction of autophagy and apoptosis. Stimulation of autophagy by lithium could contribute to the development of autophagic cell death in tumor cells.
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Affiliation(s)
- Iuliia Taskaeva
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Timakova str. 2, 630060 Novosibirsk, Russia
| | - Izabella Gogaeva
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Timakova str. 2, 630060 Novosibirsk, Russia
| | - Anastasia Shatruk
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Timakova str. 2, 630060 Novosibirsk, Russia
| | - Nataliya Bgatova
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Timakova str. 2, 630060 Novosibirsk, Russia
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26
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Russell RC, Guan KL. The multifaceted role of autophagy in cancer. EMBO J 2022; 41:e110031. [PMID: 35535466 PMCID: PMC9251852 DOI: 10.15252/embj.2021110031] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 03/20/2022] [Accepted: 04/08/2022] [Indexed: 12/15/2022] Open
Abstract
Autophagy is a cellular degradative pathway that plays diverse roles in maintaining cellular homeostasis. Cellular stress caused by starvation, organelle damage, or proteotoxic aggregates can increase autophagy, which uses the degradative capacity of lysosomal enzymes to mitigate intracellular stresses. Early studies have shown a role for autophagy in the suppression of tumorigenesis. However, work in genetically engineered mouse models and in vitro cell studies have now shown that autophagy can be either cancer-promoting or inhibiting. Here, we summarize the effects of autophagy on cancer initiation, progression, immune infiltration, and metabolism. We also discuss the efforts to pharmacologically target autophagy in the clinic and highlight future areas for exploration.
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Affiliation(s)
- Ryan C Russell
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.,Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada.,Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
| | - Kun-Liang Guan
- Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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27
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Klapan K, Simon D, Karaulov A, Gomzikova M, Rizvanov A, Yousefi S, Simon HU. Autophagy and Skin Diseases. Front Pharmacol 2022; 13:844756. [PMID: 35370701 PMCID: PMC8971629 DOI: 10.3389/fphar.2022.844756] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/22/2022] [Indexed: 12/15/2022] Open
Abstract
Autophagy is a highly conserved lysosomal degradation system that involves the creation of autophagosomes, which eventually fuse with lysosomes and breakdown misfolded proteins and damaged organelles with their enzymes. Autophagy is widely known for its function in cellular homeostasis under physiological and pathological settings. Defects in autophagy have been implicated in the pathophysiology of a variety of human diseases. The new line of evidence suggests that autophagy is inextricably linked to skin disorders. This review summarizes the principles behind autophagy and highlights current findings of autophagy's role in skin disorders and strategies for therapeutic modulation.
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Affiliation(s)
- Kim Klapan
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Dagmar Simon
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Alexander Karaulov
- Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia
| | - Marina Gomzikova
- Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Albert Rizvanov
- Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Shida Yousefi
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland.,Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia.,Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
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28
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Bradley ST, Lee YS, Gurel Z, Kimple RJ. Autophagy awakens-the myriad roles of autophagy in head and neck cancer development and therapeutic response. Mol Carcinog 2022; 61:243-253. [PMID: 34780672 PMCID: PMC8799495 DOI: 10.1002/mc.23372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 02/03/2023]
Abstract
Autophagy is an evolutionarily conserved cell survival mechanism that degrades damaged proteins and organelles to generate cellular energy during times of stress. Recycling of these cellular components occurs in a series of sequential steps with multiple regulatory points. Mechanistic dysfunction can lead to a variety of human diseases and cancers due to the complexity of autophagy and its ability to regulate vital cellular functions. The role that autophagy plays in both the development and treatment of cancer is highly complex, especially given the fact that most cancer therapies modulate autophagy. This review aims to discuss the balance of autophagy in the development, progression, and treatment of head and neck cancer, as well as highlighting the need for a deeper understanding of what is still unknown about autophagy.
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Affiliation(s)
- Samantha T Bradley
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Yong-Syu Lee
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Zafer Gurel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Randall J Kimple
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
- UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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29
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Sun Y, Cao X, Guo Y, Liu B, Zhang Y. The Prognostic and Molecular Landscape of Autophagy-Related Long Noncoding RNA in Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5614915. [PMID: 35097120 PMCID: PMC8794669 DOI: 10.1155/2022/5614915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 11/18/2021] [Indexed: 12/12/2022]
Abstract
Current evidence suggests that autophagy is closely correlated with the pathogenesis and development of malignant tumors. This study is aimed at assessing the potential prognostic significance of autophagy-related long noncoding RNA (ARlncRNA) in colorectal cancer (CRC). 3145 ARlncRNAs were obtained from autophagy-related genes (ARGs) by Pearson correlation analysis, and we established a competing endogenous RNA (ceRNA) network mediated by ARlncRNAs. A novel six-ARlncRNA prognostic signature was constructed based on TCGA samples used as the training group. Kaplan-Meier survival analysis and independent prognosis analysis were performed on the internal (training and test groups) and external validations (GEO datasets) to assess the accuracy and clinical practicability. Moreover, the nomogram combining the two independent prognostic factors (age and ARlncRNA-risk score (ARlncRNA-RS)) intuitively displayed overall survival. Gene set enrichment analysis (GSEA) conducted on the prognostic signature revealed that the gene set of the high-risk group was significantly enriched in the hallmark gene set "hypoxia" and the gene set of the low-risk group was enriched in KEGG pathways, including "peroxisome," "the citrate cycle (TCA cycle)," and "other glycan degradation." Assessment of antineoplastic therapy susceptibility and microsatellite instability (MSI) analysis were performed on CRC samples based on the prognostic signature. Moreover, Spearman correlation analysis was conducted on the expression of six ARlncRNAs of the prognostic signature and cancer stem cell (CSC) index as well as the tumor microenvironment (TME). In conclusion, this study established a six-ARlncRNA prognostic signature, which yielded favorable prognostic significance and demonstrated the correlation between ARlncRNAs and CRC progression.
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Affiliation(s)
- YuanLin Sun
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, 130021 Jilin, China
| | - XueYuan Cao
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, 130021 Jilin, China
| | - YuChen Guo
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, 130021 Jilin, China
| | - Bin Liu
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, 130021 Jilin, China
| | - Yang Zhang
- Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, 130021 Jilin, China
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30
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Bustos SO, Leal Santos N, Chammas R, Andrade LNDS. Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma. Cancers (Basel) 2022; 14:234. [PMID: 35008395 PMCID: PMC8749976 DOI: 10.3390/cancers14010234] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One way to manage such processes is through the regulation of autophagy, both in stromal and tumor cells. Autophagy is a catabolic mechanism that provides nutrients and energy, and it eliminates damaged organelles by degradation and recycling of cellular elements. Besides this primary function, autophagy plays multiple roles in the tumor microenvironment capable of affecting cell fate. Evidence demonstrates the existence of novel branches in the autophagy system related to cytoplasmic constituent's secretion. Hence, autophagy-dependent secretion assembles a tangled network of signaling that potentially contributes to metabolism reprogramming, immune regulation, and tumor progression. Here, we summarize the current awareness regarding secretory autophagy and the intersection with exosome biogenesis and release in melanoma and their role in tumor resistance. In addition, we present and discuss data from public databases concerning autophagy and exosome-related genes as important mediators of melanoma behavior. Finally, we will present the main challenges in the field and strategies to translate most of the pre-clinical findings to clinical practice.
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Affiliation(s)
- Silvina Odete Bustos
- Center for Translational Research in Oncology (LIM24), Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo 01246-000, Brazil; (N.L.S.); (R.C.)
| | | | | | - Luciana Nogueira de Sousa Andrade
- Center for Translational Research in Oncology (LIM24), Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo 01246-000, Brazil; (N.L.S.); (R.C.)
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Liang L, Huan L, Wang J, Wu Y, Huang S, He X. LncRNA RP11-295G20.2 regulates hepatocellular carcinoma cell growth and autophagy by targeting PTEN to lysosomal degradation. Cell Discov 2021; 7:118. [PMID: 34903728 PMCID: PMC8668967 DOI: 10.1038/s41421-021-00339-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 09/13/2021] [Indexed: 12/24/2022] Open
Abstract
PTEN is a crucial tumor suppressor and loss of PTEN protein is involved in various cancers. However, the detailed molecular mechanisms of PTEN loss in cancers remain elusive, especially the involvement of lncRNAs. Here, lncRNA RP11-295G20.2 is found to be significantly upregulated in hepatocellular carcinoma (HCC) and promotes the growth of liver cancer cells both in vitro and in vivo. Furthermore, RP11-295G20.2 inhibits autophagy in liver cancer cells. Interestingly, RP11-295G20.2 directly binds to the PTEN protein and leads to its degradation. RP11-295G20.2 expression is inversely correlated with PTEN protein expression in 82 TCGA/TCPA-LIHC samples. Surprisingly, RP11-295G20.2-induced PTEN degradation occurs through the lysosomal pathway instead of the proteasome pathway. RP11-295G20.2 binds to the N terminus of PTEN and facilitates the interaction of p62 with PTEN. Thus, PTEN is translocated into lysosomes and degraded. RP11-295G20.2 also influences AKT phosphorylation and forkhead box O 3a (FOXO3a) translocation into the nucleus, in turn regulating the transcription of autophagy-related genes. Collectively, RP11-295G20.2 directly binds to PTEN and enables its lysosomal degradation. This newly identified RP11-295G20.2/PTEN axis reveals an unexplored molecular mechanism regarding PTEN loss in liver cancer and might provide new therapeutic benefits for liver cancer patients.
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Affiliation(s)
- Linhui Liang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lin Huan
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiajia Wang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yangjun Wu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shenglin Huang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xianghuo He
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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32
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Deng G, Wang W, Li Y, Sun H, Chen X, Zeng F. Nomogram based on autophagy related genes for predicting the survival in melanoma. BMC Cancer 2021; 21:1258. [PMID: 34809598 PMCID: PMC8607622 DOI: 10.1186/s12885-021-08928-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 10/27/2021] [Indexed: 12/23/2022] Open
Abstract
Background Autophagy, a highly conserved lysosomal degradation pathway, is associated with the prognosis of melanoma. However, prognostic prediction models based on autophagy related genes (ARGs) have never been recognized in melanoma. In the present study, we aimed to establish a novel nomogram to predict the prognosis of melanoma based on ARGs signature and clinical parameters. Methods Data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases were extracted to identify the differentially expressed ARGs. Univariate, least absolute shrinkage and selection operator (LASSO) and multivariate analysis were used to select the prognostic ARGs. ARGs signature, age and stage were then enrolled to establish a nomogram to predict the survival probabilities of melanoma. The nomogram was evaluated by concordance index (C-index), receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis (DCA) was performed to assess the clinical benefits of the nomogram and TNM stage model. The nomogram was validated in GEO cohorts. Results Five prognostic ARGs were selected to construct ARGs signature model and validated in the GEO cohort. Kaplan-Meier survival analysis suggested that patients in high-risk group had significantly worse overall survival than those in low-risk group in TCGA cohort (P = 5.859 × 10–9) and GEO cohort (P = 3.075 × 10–9). We then established and validated a novel promising prognostic nomogram through combining ARGs signature and clinical parameters. The C-index of the nomogram was 0.717 in TCGA training cohort and 0.738 in GEO validation cohort. TCGA/GEO-based ROC curve and decision curve analysis (DCA) demonstrated that the nomogram was better than traditional TNM staging system for melanoma prognosis. Conclusion We firstly developed and validated an ARGs signature based-nomogram for individualized prognosis prediction in melanoma patients, which could assist with decision making for clinicians. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08928-9.
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Affiliation(s)
- Guangtong Deng
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Wenhua Wang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yayun Li
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Huiyan Sun
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiang Chen
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China. .,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Furong Zeng
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China. .,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, Bravo‐San Pedro JM, Cadwell K, Cecconi F, Choi AMK, Choi ME, Chu CT, Codogno P, Colombo M, Cuervo AM, Deretic V, Dikic I, Elazar Z, Eskelinen E, Fimia GM, Gewirtz DA, Green DR, Hansen M, Jäättelä M, Johansen T, Juhász G, Karantza V, Kraft C, Kroemer G, Ktistakis NT, Kumar S, Lopez‐Otin C, Macleod KF, Madeo F, Martinez J, Meléndez A, Mizushima N, Münz C, Penninger JM, Perera R, Piacentini M, Reggiori F, Rubinsztein DC, Ryan K, Sadoshima J, Santambrogio L, Scorrano L, Simon H, Simon AK, Simonsen A, Stolz A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Galluzzi L, Pietrocola F. Autophagy in major human diseases. EMBO J 2021; 40:e108863. [PMID: 34459017 PMCID: PMC8488577 DOI: 10.15252/embj.2021108863] [Citation(s) in RCA: 939] [Impact Index Per Article: 234.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
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Affiliation(s)
| | - Giulia Petroni
- Department of Radiation OncologyWeill Cornell Medical CollegeNew YorkNYUSA
| | - Ravi K Amaravadi
- Department of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
- Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer BiologyUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Andrea Ballabio
- Telethon Institute of Genetics and MedicinePozzuoliItaly
- Department of Translational Medical SciencesSection of PediatricsFederico II UniversityNaplesItaly
- Department of Molecular and Human GeneticsBaylor College of Medicine, and Jan and Dan Duncan Neurological Research InstituteTexas Children HospitalHoustonTXUSA
| | - Patricia Boya
- Margarita Salas Center for Biological ResearchSpanish National Research CouncilMadridSpain
| | - José Manuel Bravo‐San Pedro
- Faculty of MedicineDepartment Section of PhysiologyComplutense University of MadridMadridSpain
- Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED)MadridSpain
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball InstituteNew York University Grossman School of MedicineNew YorkNYUSA
- Department of MicrobiologyNew York University Grossman School of MedicineNew YorkNYUSA
- Division of Gastroenterology and HepatologyDepartment of MedicineNew York University Langone HealthNew YorkNYUSA
| | - Francesco Cecconi
- Cell Stress and Survival UnitCenter for Autophagy, Recycling and Disease (CARD)Danish Cancer Society Research CenterCopenhagenDenmark
- Department of Pediatric Onco‐Hematology and Cell and Gene TherapyIRCCS Bambino Gesù Children's HospitalRomeItaly
- Department of BiologyUniversity of Rome ‘Tor Vergata’RomeItaly
| | - Augustine M K Choi
- Division of Pulmonary and Critical Care MedicineJoan and Sanford I. Weill Department of MedicineWeill Cornell MedicineNew YorkNYUSA
- New York‐Presbyterian HospitalWeill Cornell MedicineNew YorkNYUSA
| | - Mary E Choi
- New York‐Presbyterian HospitalWeill Cornell MedicineNew YorkNYUSA
- Division of Nephrology and HypertensionJoan and Sanford I. Weill Department of MedicineWeill Cornell MedicineNew YorkNYUSA
| | - Charleen T Chu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Patrice Codogno
- Institut Necker‐Enfants MaladesINSERM U1151‐CNRS UMR 8253ParisFrance
- Université de ParisParisFrance
| | - Maria Isabel Colombo
- Laboratorio de Mecanismos Moleculares Implicados en el Tráfico Vesicular y la Autofagia‐Instituto de Histología y Embriología (IHEM)‐Universidad Nacional de CuyoCONICET‐ Facultad de Ciencias MédicasMendozaArgentina
| | - Ana Maria Cuervo
- Department of Developmental and Molecular BiologyAlbert Einstein College of MedicineBronxNYUSA
- Institute for Aging StudiesAlbert Einstein College of MedicineBronxNYUSA
| | - Vojo Deretic
- Autophagy Inflammation and Metabolism (AIMCenter of Biomedical Research ExcellenceUniversity of New Mexico Health Sciences CenterAlbuquerqueNMUSA
- Department of Molecular Genetics and MicrobiologyUniversity of New Mexico Health Sciences CenterAlbuquerqueNMUSA
| | - Ivan Dikic
- Institute of Biochemistry IISchool of MedicineGoethe UniversityFrankfurt, Frankfurt am MainGermany
- Buchmann Institute for Molecular Life SciencesGoethe UniversityFrankfurt, Frankfurt am MainGermany
| | - Zvulun Elazar
- Department of Biomolecular SciencesThe Weizmann Institute of ScienceRehovotIsrael
| | | | - Gian Maria Fimia
- Department of Molecular MedicineSapienza University of RomeRomeItaly
- Department of EpidemiologyPreclinical Research, and Advanced DiagnosticsNational Institute for Infectious Diseases ‘L. Spallanzani’ IRCCSRomeItaly
| | - David A Gewirtz
- Department of Pharmacology and ToxicologySchool of MedicineVirginia Commonwealth UniversityRichmondVAUSA
| | - Douglas R Green
- Department of ImmunologySt. Jude Children's Research HospitalMemphisTNUSA
| | - Malene Hansen
- Sanford Burnham Prebys Medical Discovery InstituteProgram of DevelopmentAging, and RegenerationLa JollaCAUSA
| | - Marja Jäättelä
- Cell Death and MetabolismCenter for Autophagy, Recycling & DiseaseDanish Cancer Society Research CenterCopenhagenDenmark
- Department of Cellular and Molecular MedicineFaculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Terje Johansen
- Department of Medical BiologyMolecular Cancer Research GroupUniversity of Tromsø—The Arctic University of NorwayTromsøNorway
| | - Gábor Juhász
- Institute of GeneticsBiological Research CenterSzegedHungary
- Department of Anatomy, Cell and Developmental BiologyEötvös Loránd UniversityBudapestHungary
| | | | - Claudine Kraft
- Institute of Biochemistry and Molecular BiologyZBMZFaculty of MedicineUniversity of FreiburgFreiburgGermany
- CIBSS ‐ Centre for Integrative Biological Signalling StudiesUniversity of FreiburgFreiburgGermany
| | - Guido Kroemer
- Centre de Recherche des CordeliersEquipe Labellisée par la Ligue Contre le CancerUniversité de ParisSorbonne UniversitéInserm U1138Institut Universitaire de FranceParisFrance
- Metabolomics and Cell Biology PlatformsInstitut Gustave RoussyVillejuifFrance
- Pôle de BiologieHôpital Européen Georges PompidouAP‐HPParisFrance
- Suzhou Institute for Systems MedicineChinese Academy of Medical SciencesSuzhouChina
- Karolinska InstituteDepartment of Women's and Children's HealthKarolinska University HospitalStockholmSweden
| | | | - Sharad Kumar
- Centre for Cancer BiologyUniversity of South AustraliaAdelaideSAAustralia
- Faculty of Health and Medical SciencesUniversity of AdelaideAdelaideSAAustralia
| | - Carlos Lopez‐Otin
- Departamento de Bioquímica y Biología MolecularFacultad de MedicinaInstituto Universitario de Oncología del Principado de Asturias (IUOPA)Universidad de OviedoOviedoSpain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)MadridSpain
| | - Kay F Macleod
- The Ben May Department for Cancer ResearchThe Gordon Center for Integrative SciencesW‐338The University of ChicagoChicagoILUSA
- The University of ChicagoChicagoILUSA
| | - Frank Madeo
- Institute of Molecular BiosciencesNAWI GrazUniversity of GrazGrazAustria
- BioTechMed‐GrazGrazAustria
- Field of Excellence BioHealth – University of GrazGrazAustria
| | - Jennifer Martinez
- Immunity, Inflammation and Disease LaboratoryNational Institute of Environmental Health SciencesNIHResearch Triangle ParkNCUSA
| | - Alicia Meléndez
- Biology Department, Queens CollegeCity University of New YorkFlushingNYUSA
- The Graduate Center Biology and Biochemistry PhD Programs of the City University of New YorkNew YorkNYUSA
| | - Noboru Mizushima
- Department of Biochemistry and Molecular BiologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Christian Münz
- Viral ImmunobiologyInstitute of Experimental ImmunologyUniversity of ZurichZurichSwitzerland
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
- Department of Medical GeneticsLife Sciences InstituteUniversity of British ColumbiaVancouverBCCanada
| | - Rushika M Perera
- Department of AnatomyUniversity of California, San FranciscoSan FranciscoCAUSA
- Department of PathologyUniversity of California, San FranciscoSan FranciscoCAUSA
- Helen Diller Family Comprehensive Cancer CenterUniversity of California, San FranciscoSan FranciscoCAUSA
| | - Mauro Piacentini
- Department of BiologyUniversity of Rome “Tor Vergata”RomeItaly
- Laboratory of Molecular MedicineInstitute of Cytology Russian Academy of ScienceSaint PetersburgRussia
| | - Fulvio Reggiori
- Department of Biomedical Sciences of Cells & SystemsMolecular Cell Biology SectionUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - David C Rubinsztein
- Department of Medical GeneticsCambridge Institute for Medical ResearchUniversity of CambridgeCambridgeUK
- UK Dementia Research InstituteUniversity of CambridgeCambridgeUK
| | - Kevin M Ryan
- Cancer Research UK Beatson InstituteGlasgowUK
- Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular MedicineCardiovascular Research InstituteRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Laura Santambrogio
- Department of Radiation OncologyWeill Cornell Medical CollegeNew YorkNYUSA
- Sandra and Edward Meyer Cancer CenterNew YorkNYUSA
- Caryl and Israel Englander Institute for Precision MedicineNew YorkNYUSA
| | - Luca Scorrano
- Istituto Veneto di Medicina MolecolarePadovaItaly
- Department of BiologyUniversity of PadovaPadovaItaly
| | - Hans‐Uwe Simon
- Institute of PharmacologyUniversity of BernBernSwitzerland
- Department of Clinical Immunology and AllergologySechenov UniversityMoscowRussia
- Laboratory of Molecular ImmunologyInstitute of Fundamental Medicine and BiologyKazan Federal UniversityKazanRussia
| | | | - Anne Simonsen
- Department of Molecular MedicineInstitute of Basic Medical SciencesUniversity of OsloOsloNorway
- Centre for Cancer Cell ReprogrammingInstitute of Clinical MedicineUniversity of OsloOsloNorway
- Department of Molecular Cell BiologyInstitute for Cancer ResearchOslo University Hospital MontebelloOsloNorway
| | - Alexandra Stolz
- Institute of Biochemistry IISchool of MedicineGoethe UniversityFrankfurt, Frankfurt am MainGermany
- Buchmann Institute for Molecular Life SciencesGoethe UniversityFrankfurt, Frankfurt am MainGermany
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and BiotechnologyFoundation for Research and Technology‐HellasHeraklion, CreteGreece
- Department of Basic SciencesSchool of MedicineUniversity of CreteHeraklion, CreteGreece
| | - Sharon A Tooze
- Molecular Cell Biology of AutophagyThe Francis Crick InstituteLondonUK
| | - Tamotsu Yoshimori
- Department of GeneticsGraduate School of MedicineOsaka UniversitySuitaJapan
- Department of Intracellular Membrane DynamicsGraduate School of Frontier BiosciencesOsaka UniversitySuitaJapan
- Integrated Frontier Research for Medical Science DivisionInstitute for Open and Transdisciplinary Research Initiatives (OTRI)Osaka UniversitySuitaJapan
| | - Junying Yuan
- Interdisciplinary Research Center on Biology and ChemistryShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghaiChina
- Department of Cell BiologyHarvard Medical SchoolBostonMAUSA
| | - Zhenyu Yue
- Department of NeurologyFriedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Qing Zhong
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationDepartment of PathophysiologyShanghai Jiao Tong University School of Medicine (SJTU‐SM)ShanghaiChina
| | - Lorenzo Galluzzi
- Department of Radiation OncologyWeill Cornell Medical CollegeNew YorkNYUSA
- Sandra and Edward Meyer Cancer CenterNew YorkNYUSA
- Caryl and Israel Englander Institute for Precision MedicineNew YorkNYUSA
- Department of DermatologyYale School of MedicineNew HavenCTUSA
- Université de ParisParisFrance
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Jacquet M, Hervouet E, Baudu T, Herfs M, Parratte C, Feugeas JP, Perez V, Reynders C, Ancion M, Vigneron M, Baguet A, Guittaut M, Fraichard A, Despouy G. GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback. BIOLOGY 2021; 10:biology10100956. [PMID: 34681055 PMCID: PMC8533302 DOI: 10.3390/biology10100956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/10/2021] [Accepted: 09/14/2021] [Indexed: 12/03/2022]
Abstract
Simple Summary Epithelial–mesenchymal transition (EMT) is involved in metastasis formation, chemoresistance, apoptosis resistance, and acquisition of stem cell properties, making this process an attractive target in cancer. However, direct targeting of EMT remains challenging. Autophagy—an intracellular mechanism—has been noted to be involved in the regulation of EMT—mainly by its involvement in the degradation of EMT actors, explaining why understanding of how autophagy could regulate EMT might be promising in the development of new cancer therapies. Here, we found that GABARAPL1—an autophagy-related gene—was increased in human NSCLC mesenchymal tumors compared to epithelial tumors, and induction of EMT in an A549 lung cancer cell line by TGF-β/TNF-α cytokines also led to an increase in GABARAPL1 expression. This regulation could involve the EMT-related transcription factors of the SMAD family. To understand the role of GABARAPL1 in EMT regulation in lung cancer cells, A549 KO GABARAPL1 were designed and used to investigate whether GABARAPL1 could inhibit EMT via its involvement in SMAD degradation. The results indicate that GABARAPL1-mediated autophagic degradation could intervene as a negative EMT-regulatory loop. Abstract The pathway of selective autophagy, leading to a targeted elimination of specific intracellular components, is mediated by the ATG8 proteins, and has been previously suggested to be involved in the regulation of the Epithelial–mesenchymal transition (EMT) during cancer’s etiology. However, the molecular factors and steps of selective autophagy occurring during EMT remain unclear. We therefore analyzed a cohort of lung adenocarcinoma tumors using transcriptome analysis and immunohistochemistry, and found that the expression of ATG8 genes is correlated with that of EMT-related genes, and that GABARAPL1 protein levels are increased in EMT+ tumors compared to EMT- ones. Similarly, the induction of EMT in the A549 lung adenocarcinoma cell line using TGF-β/TNF-α led to a high increase in GABARAPL1 expression mediated by the EMT-related transcription factors of the SMAD family, whereas the other ATG8 genes were less modified. To determine the role of GABARAPL1 during EMT, we used the CRISPR/Cas9 technology in A549 and ACHN kidney adenocarcinoma cell lines to deplete GABARAPL1. We then observed that GABARAPL1 knockout induced EMT linked to a defect of GABARAPL1-mediated degradation of the SMAD proteins. These findings suggest that, during EMT, GABARAPL1 might intervene in an EMT-regulatory loop. Indeed, induction of EMT led to an increase in GABARAPL1 levels through the activation of the SMAD signaling pathway, and then GABARAPL1 induced the autophagy-selective degradation of SMAD proteins, leading to EMT inhibition.
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Affiliation(s)
- Marine Jacquet
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
| | - Eric Hervouet
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
- DImaCellplatform, Université Bourgogne Franche-Comté, F-25000 Besançon, France
- EPIGENExp, Université Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Timothée Baudu
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
| | - Michaël Herfs
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000 Liege, Belgium; (M.H.); (C.R.); (M.A.)
| | - Chloé Parratte
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
| | - Jean-Paul Feugeas
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
| | - Valérie Perez
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
| | - Célia Reynders
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000 Liege, Belgium; (M.H.); (C.R.); (M.A.)
| | - Marie Ancion
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000 Liege, Belgium; (M.H.); (C.R.); (M.A.)
| | - Marc Vigneron
- Team Replisome Dynamics and Cancer, UMR7242 Biotechnologie et Signalisation Cellulaire, Ecole Supérieure de Biotechnologie de Strasbourg, CNRS-Université de Strasbourg, F-67412 Illkirch, France;
| | - Aurélie Baguet
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
| | - Michaël Guittaut
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
- DImaCellplatform, Université Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Annick Fraichard
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
| | - Gilles Despouy
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France; (M.J.); (E.H.); (T.B.); (C.P.); (J.-P.F.); (V.P.); (A.B.); (M.G.); (A.F.)
- Correspondence:
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Hill D, Cosgarea I, Reynolds N, Lovat P, Armstrong J. Research Techniques Made Simple: Analysis of Autophagy in the Skin. J Invest Dermatol 2021; 141:5-9.e1. [PMID: 33342508 DOI: 10.1016/j.jid.2020.10.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/21/2020] [Accepted: 10/11/2020] [Indexed: 02/05/2023]
Abstract
Autophagy is required for normal skin homeostasis and its disordered regulation is implicated in a range of cutaneous diseases. Several well-characterized biomarkers of autophagy are used experimentally to quantify autophagic activity or clinically to correlate autophagy with disease progression. This article discusses the advantages and limitations of different approaches for measuring autophagy as well as the techniques for modulating autophagy. These include analysis of endogenous LC3, a central autophagy regulatory protein, and measurement of LC3 flux using a dual-fluorescent reporter, which provides a quantitative readout of autophagy in cell culture systems in vitro and animal models in vivo. Degradation of SQSTM1/p62 during autophagy is proposed as an alternative biomarker allowing the analysis of autophagy both experimentally and clinically. However, the complex regulation of individual autophagy proteins and their involvement in multiple pathways means that several proteins must be analyzed together, preferably over a time course to accurately interpret changes in autophagic activity. Genetic modification of autophagy proteins can be used to better understand basic autophagic mechanisms contributing to health and disease, whereas small molecule inhibitors of autophagy regulatory proteins, lysosomal inhibitors, or activators of cytotoxic autophagy have been explored as potential treatments for skin disorders where autophagy is defective.
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Affiliation(s)
- David Hill
- Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, United Kingdom
| | - Ioana Cosgarea
- Translation and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle Dermatology, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom; Newcastle Oncology, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Nick Reynolds
- Translation and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle Dermatology, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Penny Lovat
- Translation and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; AMLo Biosciences Ltd, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Jane Armstrong
- Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, United Kingdom.
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Frangež Ž, Gérard D, He Z, Gavriil M, Fernández-Marrero Y, Seyed Jafari SM, Hunger RE, Lucarelli P, Yousefi S, Sauter T, Sinkkonen L, Simon HU. ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1. Front Oncol 2021; 11:721624. [PMID: 34458153 PMCID: PMC8397460 DOI: 10.3389/fonc.2021.721624] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/26/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy is a highly conserved cellular process in which intracellular proteins and organelles are sequestered and degraded after the fusion of double-membrane vesicles known as autophagosomes with lysosomes. The process of autophagy is dependent on autophagy-related (ATG) proteins. The role of autophagy in cancer is very complex and still elusive. We investigated the expression of ATG proteins in benign nevi, primary and metastatic melanoma tissues using customized tissue microarrays (TMA). Results from immunohistochemistry show that the expression of ATG5 and ATG7 is significantly reduced in melanoma tissues compared to benign nevi. This reduction correlated with changes in the expression of autophagic activity markers, suggesting decreased basal levels of autophagy in primary and metastatic melanomas. Furthermore, the analysis of survival data of melanoma patients revealed an association between reduced ATG5 and ATG7 levels with an unfavourable clinical outcome. Currently, the mechanisms regulating ATG expression levels in human melanoma remains unknown. Using bioinformatic predictions of transcription factor (TF) binding motifs in accessible chromatin of primary melanocytes, we identified new TFs involved in the regulation of core ATGs. We then show that nuclear respiratory factor 1 (NRF1) stimulates the production of mRNA and protein as well as the promoter activity of ATG5 and ATG7. Moreover, NRF1 deficiency increased in vitro migration of melanoma cells. Our results support the concept that reduced autophagic activity contributes to melanoma development and progression, and identifies NRF1 as a novel TF involved in the regulation of both ATG5 and ATG7 genes.
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Affiliation(s)
- Živa Frangež
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Deborah Gérard
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Zhaoyue He
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Marios Gavriil
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Yuniel Fernández-Marrero
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Biological Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Science Centre, Toronto, ON, Canada
| | - S. Morteza Seyed Jafari
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Robert E. Hunger
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Philippe Lucarelli
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Shida Yousefi
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Thomas Sauter
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Lasse Sinkkonen
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Institute of Biochemistry, Medical School Brandenburg, Neuruppin, Germany
- Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia
- Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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Li Y, Yang G, Yang C, Tang P, Chen J, Zhang J, Liu J, Ouyang L. Targeting Autophagy-Related Epigenetic Regulators for Cancer Drug Discovery. J Med Chem 2021; 64:11798-11815. [PMID: 34378389 DOI: 10.1021/acs.jmedchem.1c00579] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Existing evidence has demonstrated that epigenetic modifications (including DNA methylation, histone modifications, and microRNAs), which are associated with the occurrence and development of tumors, can directly or indirectly regulate autophagy. In particular, nuclear events induced by several epigenetic regulators can regulate the autophagic process and expression levels of tumor-associated genes, thereby promoting tumor progression. Tumor-associated microRNAs, including oncogenic and tumor-suppressive microRNAs, are of great significance to autophagy during tumor progression. Targeting autophagy with emerging epigenetic drugs is expected to be a promising therapeutic strategy for human tumors. From this perspective, we aim to summarize the role of epigenetic modification in the autophagic process and the underlying molecular mechanisms of tumorigenesis. Furthermore, the regulatory efficacy of epigenetic drugs on the autophagic process in tumors is also summarized. This perspective may provide a theoretical basis for the combined treatment of epigenetic drugs/autophagy mediators in tumors.
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Affiliation(s)
- Yang Li
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Gaoxia Yang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Chengcan Yang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Pan Tang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Juncheng Chen
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Jifa Zhang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
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Autophagy Inhibition in BRAF-Driven Cancers. Cancers (Basel) 2021; 13:cancers13143498. [PMID: 34298710 PMCID: PMC8306561 DOI: 10.3390/cancers13143498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/10/2021] [Accepted: 07/11/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary BRAF is a protein kinase that is frequently mutationally activated in cancer. Mutant BRAF can be pharmacologically inhibited, which in combination with blockade of its direct effector, MEK1/2, is an FDA-approved therapeutic strategy for several BRAF-mutated cancer patients, such as melanoma, non-small-cell lung carcinoma, and thyroid cancer. However, therapy resistance is a major clinical challenge, highlighting the need for comprehensive investigations on the biological causes of such resistance, as well as to develop novel therapeutic strategies to improve patient survival. Autophagy is a cellular recycling process, which has been shown to allow cancer cells to escape from BRAF inhibition. Combined blockade of autophagy and BRAF signaling is a novel therapeutic strategy that is currently being tested in clinical trials. This review describes the relationship between BRAF-targeted therapy and autophagy regulation and discusses possible future treatment strategies. Abstract Several BRAF-driven cancers, including advanced BRAFV600E/K-driven melanoma, non-small-cell lung carcinoma, and thyroid cancer, are currently treated using first-line inhibitor combinations of BRAFV600E plus MEK1/2. However, despite the success of this vertical inhibition strategy, the durability of patient response is often limited by the phenomenon of primary or acquired drug resistance. It has recently been shown that autophagy, a conserved cellular recycling process, is increased in BRAF-driven melanoma upon inhibition of BRAFV600E signaling. Autophagy is believed to promote tumor progression of established tumors and also to protect cancer cells from the cytotoxic effects of chemotherapy. To this end, BRAF inhibitor (BRAFi)-resistant cells often display increased autophagy compared to responsive lines. Several mechanisms have been proposed for BRAFi-induced autophagy, such as activation of the endoplasmic reticulum (ER) stress gatekeeper GRP78, AMP-activated protein kinase, and transcriptional regulation of the autophagy regulating transcription factors TFEB and TFE3 via ERK1/2 or mTOR inhibition. This review describes the relationship between BRAF-targeted therapy and autophagy regulation, and discusses possible future treatment strategies of combined inhibition of oncogenic signaling plus autophagy for BRAF-driven cancers.
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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Krag TO, Holm-Yildiz S, Witting N, Vissing J. Autophagy is affected in patients with hypokalemic periodic paralysis: an involvement in vacuolar myopathy? Acta Neuropathol Commun 2021; 9:109. [PMID: 34120654 PMCID: PMC8201813 DOI: 10.1186/s40478-021-01212-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/07/2021] [Indexed: 11/18/2022] Open
Abstract
Hypokalemic periodic paralysis is an autosomal dominant, rare disorder caused by variants in the genes for voltage-gated calcium channel CaV1.1 (CACNA1S) and NaV1.4 (SCN4A). Patients with hypokalemic periodic paralysis may suffer from periodic paralysis alone, periodic paralysis co-existing with permanent weakness or permanent weakness alone. Hypokalemic periodic paralysis has been known to be associated with vacuolar myopathy for decades, and that vacuoles are a universal feature regardless of phenotype. Hence, we wanted to investigate the nature and cause of the vacuoles. Fourteen patients with the p.R528H variation in the CACNA1S gene was included in the study. Histology, immunohistochemistry and transmission electron microscopy was used to assess general histopathology, ultrastructure and pattern of expression of proteins related to muscle fibres and autophagy. Western blotting and real-time PCR was used to determine the expression levels of proteins and mRNA of the proteins investigated in immunohistochemistry. Histology and transmission electron microscopy revealed heterogenous vacuoles containing glycogen, fibrils and autophagosomes. Immunohistochemistry demonstrated autophagosomes and endosomes arrested at the pre-lysosome fusion stage. Expression analysis showed a significant decrease in levels of proteins an mRNA involved in autophagy in patients, suggesting a systemic effect. However, activation level of the master regulator of autophagy gene transcription, TFEB, did not differ between patients and controls, suggesting competing control over autophagy gene transcription by nutritional status and calcium concentration, both controlling TFEB activity. The findings suggest that patients with hypokalemic periodic paralysis have disrupted autophagic processing that contribute to the vacuoles seen in these patients.
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Rosenfeldt MT, O'Prey J, Lindsay CR, Nixon C, Roth S, Sansom OJ, Ryan KM. Loss of autophagy affects melanoma development in a manner dependent on PTEN status. Cell Death Differ 2021; 28:1437-1439. [PMID: 33664481 PMCID: PMC8027884 DOI: 10.1038/s41418-021-00746-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 01/15/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022] Open
Affiliation(s)
- Mathias T Rosenfeldt
- Cancer Research UK Beatson Institute, Glasgow, UK.
- Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.
- Department of Pathology, University of Wuerzburg, Wuerzburg, Germany.
| | - Jim O'Prey
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Sabine Roth
- Department of Pathology, University of Wuerzburg, Wuerzburg, Germany
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Kevin M Ryan
- Cancer Research UK Beatson Institute, Glasgow, UK.
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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Saoudaoui S, Bernard M, Cardin GB, Malaquin N, Christopoulos A, Rodier F. mTOR as a senescence manipulation target: A forked road. Adv Cancer Res 2021; 150:335-363. [PMID: 33858600 DOI: 10.1016/bs.acr.2021.02.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Cellular senescence, cancer and aging are highly interconnected. Among many important molecular machines that lie at the intersection of this triad, the mechanistic (formerly mammalian) target of rapamycin (mTOR) is a central regulator of cell metabolism, proliferation, and survival. The mTOR signaling cascade is essential to maintain cellular homeostasis in normal biological processes or in response to stress, and its dysregulation is implicated in the progression of many disorders, including age-associated diseases. Accordingly, the pharmacological implications of mTOR inhibition using rapamycin or others rapalogs span the treatment of various human diseases from immune disorders to cancer. Importantly, rapamycin is one of the only known pan-species drugs that can extend lifespan. The molecular and cellular mechanisms explaining the phenotypic consequences of mTOR are vast and heavily studied. In this review, we will focus on the potential role of mTOR in the context of cellular senescence, a tumor suppressor mechanism and a pillar of aging. We will explore the link between senescence, autophagy and mTOR and discuss the opportunities to exploit senescence-associated mTOR functions to manipulate senescence phenotypes in age-associated diseases and cancer treatment.
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Affiliation(s)
- Sarah Saoudaoui
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada
| | - Monique Bernard
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada
| | - Guillaume B Cardin
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada
| | - Nicolas Malaquin
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada
| | - Apostolos Christopoulos
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada; Otolaryngology-Head and Neck Surgery Service, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada
| | - Francis Rodier
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada; Université de Montréal, Département de radiologie, radio-oncologie et médicine nucléaire, Montreal, QC, Canada.
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Frangež Ž, Seyed Jafari SM, Hunger RE, Simon HU. Loss of Concurrent Regulation of the Expression of BIF-1, BAX, and Beclin-1 in Primary and Metastatic Melanoma. BIOCHEMISTRY (MOSCOW) 2021; 85:1227-1234. [PMID: 33202207 DOI: 10.1134/s0006297920100107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Melanoma is one of the most aggressive and drug-resistant cancers. Despite novel promising therapeutic strategies, the prognosis of metastatic melanoma patients remains poor and it is often associated with high relapse rates. Endophilin B1, also known as BIF-1, is a multifunctional protein involved in several biological processes such as autophagy and apoptosis. BIF-1 promotes apoptosis through binding to BAX and its translocation to the mitochondrial outer membrane. On the other hand, BIF-1 can interact with Beclin-1 through UVRAG to promote autophagy. Several reports suggest an ambiguous role of BIF-1 in cancer development and progression. For example, it has been demonstrated that the expression of BIF-1 is reduced in both primary and metastatic melanoma and that the reduction of BIF-1 expression is associated with reduced overall survival of melanoma patients. Here we show that the expression of Beclin-1 and active form of BAX are also reduced in the melanoma patients. However, while we observed strong positive correlations between the expression of BIF-1 and Beclin-1 as well as between BIF-1 and BAX in benign nevi, these correlations were lost in the primary and metastatic melanoma cells. These data indicate disruption in the proximal molecular mechanisms which regulate expression of BIF-1, Beclin-1, and BAX in the primary and metastatic melanoma.
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Affiliation(s)
- Ž Frangež
- Institute of Pharmacology, University of Bern, Bern, 3010, Switzerland
| | - S M Seyed Jafari
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, 3010, Switzerland
| | - R E Hunger
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, 3010, Switzerland
| | - H-U Simon
- Institute of Pharmacology, University of Bern, Bern, 3010, Switzerland. .,Department of Clinical Immunology and Allergology, Sechenov University, Moscow, 119435, Russia
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Lee XC, Werner E, Falasca M. Molecular Mechanism of Autophagy and Its Regulation by Cannabinoids in Cancer. Cancers (Basel) 2021; 13:cancers13061211. [PMID: 33802014 PMCID: PMC7999886 DOI: 10.3390/cancers13061211] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This review examines the complex function of autophagy in malignancy and explores its regulation by cannabinoids in different cancers. Autophagy is an important process in the maintenance of cellular homeostasis, through the degradation and recycling of cytoplasmic constituents. The action of autophagy is highly dependent on tumour stage and type and the receptors with which ligands interact. Cannabinoids are growingly being acknowledged for their anticancer activities and are known to stimulate several mechanisms such as apoptosis and autophagy. Better understanding the mechanism of action behind autophagy and its regulation by cannabinoids will allow the development of novel cancer therapeutics. Abstract Autophagy is a “self-degradation” process whereby malfunctioned cytoplasmic constituents and protein aggregates are engulfed by a vesicle called the autophagosome, and subsequently degraded by the lysosome. Autophagy plays a crucial role in sustaining protein homeostasis and can be an alternative source of energy under detrimental circumstances. Studies have demonstrated a paradoxical function for autophagy in cancer, displaying both tumour suppressive and tumour promotive roles. In early phases of tumour development autophagy promotes cancer cell death. In later phases, autophagy enables cancer cells to survive and withstand therapy. Cannabinoids, which are derivatives of the Cannabis sativa L. plant, have shown to be associated with autophagy induction in cells. There is an emerging interest in studying the signalling pathways involved in cannabinoid-induced autophagy and their potential application in anticancer therapies. In this review, the molecular mechanisms involved in the autophagy degradation process will be discussed. This review also highlights a role for autophagy in cancer progression, with cannabinoid-induced autophagy presenting a novel strategy for anticancer therapy.
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Abstract
The immune system can recognize tumor cells to mount antigen-specific T cell response. Central to the establishment of T cell-mediated adaptive immunity are the inflammatory events that facilitate antigen presentation by stimulating the expression of MHC and costimulatory molecules and the secretion of pro-inflammatory cytokines. Such inflammatory events can be triggered upon cytotoxic treatments that induce immunogenic cancer cell death modalities. However, cancers have acquired a plethora of mechanisms to subvert, or to hide from, host-encoded immunosurveillance. Here, we discuss how tumor intrinsic oncogenic factors subvert desirable intratumoral inflammation by suppressing immunogenic cell death.
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Affiliation(s)
- Samuel T Workenhe
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Jonathan Pol
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,Inserm U1138, Paris, France.,Equipe 11 Labellisée Par La Ligue Nationale Contre Le Cancer, Centre De Recherche Des Cordeliers, Paris, France.,Université De Paris, Paris, France.,Sorbonne Université, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Guido Kroemer
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,Inserm U1138, Paris, France.,Equipe 11 Labellisée Par La Ligue Nationale Contre Le Cancer, Centre De Recherche Des Cordeliers, Paris, France.,Université De Paris, Paris, France.,Sorbonne Université, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.,Institut Universitaire De France, Paris, France.,Pôle De Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.,Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.,Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
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Acute Increases in Intracellular Zinc Lead to an Increased Lysosomal and Mitochondrial Autophagy and Subsequent Cell Demise in Malignant Melanoma. Int J Mol Sci 2021; 22:ijms22020667. [PMID: 33440911 PMCID: PMC7826594 DOI: 10.3390/ijms22020667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/28/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023] Open
Abstract
Changes in zinc content and dysregulated zinc homeostatic mechanisms have been recognized in several solid malignancies such as prostate cancer, breast cancer, or pancreatic cancer. Moreover, it has been shown that zinc serum and/or tissue levels are altered in melanoma with varying effects on melanoma development and biology. This study was conducted to explore the effects of acute increases of intracellular zinc in a set of melanoma tissue explants obtained from clinical samples. Measurements of their zinc content showed an extant heterogeneity in total and free intracellular zinc pools associated with varying biological behavior of individual cells, e.g., autophagy levels and propensity to cell death. Use of zinc pyrithione elevated intracellular zinc in a short time frame which resulted in marked changes in mitochondrial activity and lysosomes. These alterations were accompanied by significantly enhanced autophagy flux and subsequent cell demise in the absence of typical apoptotic cell death markers. The present results show for the first time that acutely increased intracellular zinc in melanoma cells specifically enhances their autophagic activity via mitochondria and lysosomes which leads to autophagic cell death. While biologically relevant, this discovery may contribute to our understanding and exploration of zinc in relation to autophagy as a means of controlling melanoma growth and survival.
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Bhol CS, Panigrahi DP, Praharaj PP, Mahapatra KK, Patra S, Mishra SR, Behera BP, Bhutia SK. Epigenetic modifications of autophagy in cancer and cancer therapeutics. Semin Cancer Biol 2020; 66:22-33. [DOI: 10.1016/j.semcancer.2019.05.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 05/09/2019] [Accepted: 05/30/2019] [Indexed: 12/30/2022]
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Rahmati M, Ebrahim S, Hashemi S, Motamedi M, Moosavi MA. New insights on the role of autophagy in the pathogenesis and treatment of melanoma. Mol Biol Rep 2020; 47:9021-9032. [DOI: 10.1007/s11033-020-05886-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
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Najafzadeh B, Asadzadeh Z, Motafakker Azad R, Mokhtarzadeh A, Baghbanzadeh A, Alemohammad H, Abdoli Shadbad M, Vasefifar P, Najafi S, Baradaran B. The oncogenic potential of NANOG: An important cancer induction mediator. J Cell Physiol 2020; 236:2443-2458. [PMID: 32960465 DOI: 10.1002/jcp.30063] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022]
Abstract
Cancer stem cells (CSCs) are a unique population in the tumor, but they only comprise 2%-5% of the tumor bulk. Although CSCs share several features with embryonic stem cells, CSCs can give rise to the tumor cells. CSCs overexpress embryonic transcription factor NANOG, which is downregulated in differentiated tissues. This transcription factor confers CSC's stemness, unlimited self-renewal, metastasis, invasiveness, angiogenesis, and drug-resistance with the assistance of WNT, OCT4, SOX2, Hedgehog, BMI-1, and other complexes. NANOG facilitates CSCs development via multiple pathways, like angiogenesis and lessening E-cadherin expression levels, which paves the road for metastasis. Moreover, NANOG represses apoptosis and leads to drug-resistance. This review aims to highlight the pivotal role of NANOG and the pertained pathways in CSCs. Also, this current study intends to demonstrate that targeting NANOG can dimmish the CSCs, sensitize the tumor to chemotherapy, and eradicate the cancer cells.
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Affiliation(s)
- Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Parisa Vasefifar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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50
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Molecular mechanisms of interplay between autophagy and metabolism in cancer. Life Sci 2020; 259:118184. [PMID: 32763290 DOI: 10.1016/j.lfs.2020.118184] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 07/26/2020] [Accepted: 07/28/2020] [Indexed: 12/19/2022]
Abstract
Autophagy is an essential mechanism of cellular degradation, a way to protect the cells under stress conditions, such as deprivation of nutrients, growth factors and cellular damage. However, in normal physiology autophagy plays a significant role in cancer cells. Current research is in progress to understand how autophagy and cancer cells go hand in hand to support cancer cell progression. The important aspect in cancer and autophagy is the interdependence of autophagy in the survival and progression of cancer cells. Autophagy is known to be a major cause of chemotherapeutic resistance in various cancer cell types. Therefore, inhibition of autophagy as an effective therapeutic approach is being actively studied and tested in clinical studies. Multiple metabolic pathways are linked with autophagy that could potentially be a significant target for chemotherapeutic strategy. The comprehension of the interconnection of autophagy with cancer metabolism can pave a novel findings for effective combinatorial therapeutic strategies.
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