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Huang JC, Tong XL, Xiang MSW, Boumelhem BB, Foulis DP, Zhang M, McKenzie CA, McCaughan GW, Reinheckel T, Zhang HE, Gorrell MD. Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in experimental primary liver cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167819. [PMID: 40187163 DOI: 10.1016/j.bbadis.2025.167819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 03/13/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers Nfkbib, Cxcl10 and Ccl5 were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, via mechanisms that may include increased autophagy and tumour suppression.
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MESH Headings
- Animals
- Hepatocytes/pathology
- Hepatocytes/metabolism
- Hepatocytes/enzymology
- Mice
- Mice, Knockout
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/deficiency
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/chemically induced
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Male
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Diet, High-Fat/adverse effects
- Mice, Inbred C57BL
- Inflammasomes/metabolism
- Liver/pathology
- Liver/metabolism
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Affiliation(s)
- JiaLi Carrie Huang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Xinlin Linda Tong
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Michelle Sui Wen Xiang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Badwi B Boumelhem
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Diarmid P Foulis
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - MingChang Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Catriona A McKenzie
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Geoffrey W McCaughan
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), partner site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany
| | - Hui E Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Mark D Gorrell
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
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Zhou W, Zhang J, Lu X, Zhao Z, Weng Y, Zhu C. Umbilical cord mesenchymal stem cell-derived extracellular vesicles improve excessive autophagy of granulosa cells through METTL3. Am J Physiol Cell Physiol 2025; 328:C1586-C1604. [PMID: 40106233 DOI: 10.1152/ajpcell.00785.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/11/2024] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting women's fertility. We assessed the effect of umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) on PTEN-induced kinase 1 (PINK1)/Parkin-mediated excessive autophagy of ovarian granulosa cells (GCs) through methyltransferase-like 3 (METTL3). Human ovarian GC line KGN was cultured and treated with dehydroepiandrosterone (DHEA) and UC-MSC-EVs. Cell apoptosis and viability, autophagy-related protein levels, adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) level, and microtubule-associated protein 1 light chain 3 β (LC3B) and translocase of outer mitochondrial membrane 20 (TOMM20) colocalization were assessed by flow cytometry, CCK-8, Western blot, kit, and immunofluorescence. PINK1 N6-methyladenosine (m6A) modification, METTL3 levels, and PINK1 mRNA stability were determined by methylated RNA immunoprecipitation, reverse transcription quantitative polymerase chain reaction, and Western blot. The PCOS mouse model was established and treated with UC-MSC-EVs. Serum hormone and ovarian tissue autophagy-related protein levels were determined by enzyme-linked immunosorbent assay. DHEA decreased KGN cell viability and p62 level, increased PINK1, Parkin, LC3BII/I, and Beclin-1 protein levels, ATP content, MMP level, TOMM20+LC3B+ cell number, and apoptosis, which were partly abrogated by UC-MSC-EV treatment. PINK1 had m6A modification sites. METTL3 was a PINK1 m6A-modified writer protein. After DHEA treatment, KGN cells showed elevated METTL3 and PINK1 m6A modification levels and mRNA stability, whereas UC-MSC-EV treatment caused the opposite results. METTL3 overexpression partly averted UC-MSC-EVs-improved PINK1/Parkin-mediated mitophagy. UC-MSC-EVs curbed PINK1/Parkin-mediated excessive autophagy through METTL3 and improved ovarian function in PCOS mice. In conclusion, UC-MSC-EVs suppressed PINK1/Parkin-mediated mitophagy of ovarian GCs through METTL3, thereby improving PCOS.NEW & NOTEWORTHY Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting women's fertility. The authors in this study using DHEA-induced granulosa cells (GCs) demonstrated that umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) suppressed PINK1/Parkin-mediated mitophagy of ovarian GCs through METTL3, thereby improving PCOS.
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Affiliation(s)
- Weiqin Zhou
- Reproductive Medicine Center, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Ju Zhang
- Reproductive Medicine Center, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Xuanping Lu
- Reproductive Medicine Center, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Ziwei Zhao
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Yujing Weng
- Department of Gynaecology and Obstetrics, Suzhou Xihua Maternal and Child Health Hospital, Suzhou, People's Republic of China
| | - Chunrong Zhu
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
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Ercin N, Besli N, Johnson BS, Cakmak RK, Beker M, Beker MC, Celik U. Investigation of the Effects of Acacetin on Autophagy Pathway and Exosome Release in Amyloid Beta Peptide-Induced Toxicity Models. Mol Neurobiol 2025:10.1007/s12035-025-04908-3. [PMID: 40257688 DOI: 10.1007/s12035-025-04908-3] [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: 01/22/2024] [Accepted: 04/01/2025] [Indexed: 04/22/2025]
Abstract
Understanding the mechanism behind Alzheimer's disease is imperative due to the critical role of the autophagy pathway in protein homeostasis and neuronal survival. Autophagy pathway irregularities in neurons may increase exosome-mediated toxic protein transport, which can spread neurodegenerative diseases. Compelling evidence hints that acacetin (ACA) is a naturally occurring biocomponent exhibiting neuroprotective pharmacological properties. However, further molecular investigations are pressing to uncover the therapeutic potential of ACA. The present investigation endeavors to scrutinize the impact of ACA on the autophagy pathway and exosome release in an amyloid beta (Aβ) peptide-induced toxicity model. Herein, first, molecular modeling was performed between ACA and autophagy-related proteins. Afterward, the Aβ peptide-induced toxicity model cells were treated with ACA, and total and exosomal protein isolation was carried out and analyzed. Considering the findings, our molecular dynamics simulation of the ACA-protein complexes, spanning 100 ns, conclusively demonstrated stable protein-ligand interactions. Additionally, ACA was determined to regulate LC3II, Beclin-1, p62, and Lamp2a protein levels and reduce amyloid-β and Alix protein levels. In conclusion, our study highlights the significant in vitro neuroprotective effect of ACA against Aβ toxicity through autophagy. Moving forward, future studies may seek to elucidate the specific neuroprotective, therapeutic effects and mechanisms of ACA via autophagy in in vivo models. Addressing the identified limitations and capitalizing on the outlined future prospects are essential steps towards harnessing the therapeutic potential of ACA in combating neurodegenerative diseases, offering renewed hope for patients and caregivers alike.
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Affiliation(s)
- Nilufer Ercin
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Nail Besli
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Bahar Sarikamis Johnson
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Rabia Kalkan Cakmak
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Merve Beker
- Department of Medical Biology, Hamidiye International School of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Mustafa C Beker
- Department of Physiology, School of Medicine, Istanbul Medeniyet University, Istanbul, Turkey
- Research Institute for Health Sciences and Technologies (SABITA), Regenerative and Restorative Medicine Research Center (REMER), Istanbul Medipol University, Istanbul, Turkey
| | - Ulkan Celik
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey.
- Department of Medical Biology, Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey.
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Sonsalla MM, Babygirija R, Johnson M, Cai S, Cole M, Yeh CY, Grunow I, Liu Y, Vertein D, Calubag MF, Trautman ME, Green CL, Rigby MJ, Puglielli L, Lamming DW. Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease. GeroScience 2025; 47:1569-1591. [PMID: 39271570 PMCID: PMC11978593 DOI: 10.1007/s11357-024-01337-3] [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: 06/26/2024] [Accepted: 08/31/2024] [Indexed: 09/15/2024] Open
Abstract
Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition in females, suggesting that the benefits of acarbose on AD may be largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a WD.
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Affiliation(s)
- Michelle M Sonsalla
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
- Comparative Biomedical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Reji Babygirija
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
- Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Madeline Johnson
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Samuel Cai
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Mari Cole
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Chung-Yang Yeh
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Isaac Grunow
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Yang Liu
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Diana Vertein
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
| | - Mariah F Calubag
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
- Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Michaela E Trautman
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
- Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Cara L Green
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Michael J Rigby
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Luigi Puglielli
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
- Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Dudley W Lamming
- Department of Medicine, University of Wisconsin-Madison, 1685 Highland Ave, MFCB Rm 4147, Madison, WI, 53705, USA.
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
- Comparative Biomedical Sciences, University of Wisconsin-Madison, Madison, WI, USA.
- Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, WI, USA.
- Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
- University of Wisconsin Carbone Cancer Center, Madison, WI, 53705, USA.
- University of Wisconsin-Madison Comprehensive Diabetes Center, Madison, WI, 53705, USA.
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Yang X, Cao X, Zhu Q. p62/SQSTM1 in cancer: phenomena, mechanisms, and regulation in DNA damage repair. Cancer Metastasis Rev 2025; 44:33. [PMID: 39954143 PMCID: PMC11829845 DOI: 10.1007/s10555-025-10250-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/06/2025] [Indexed: 02/17/2025]
Abstract
The multidomain protein cargo adaptor p62, also known as sequestosome 1, serves as a shuttling factor and adaptor for the degradation of substrates via the proteasome and autophagy pathways. Regarding its structure, p62 is composed of several functional domains, including the N-terminal Phox1 and Bem1p domains, a ZZ-type zinc finger domain, a LIM protein-binding domain that contains the tumor necrosis factor receptor-associated factor 6 (TRAF6) binding region, two nuclear localization signals (NLS 1/2), a nuclear export signal (NES), the LC3-interacting region (LIR), a Kelch-like ECH-associated protein 1 (KEAP1)-interacting region, and a ubiquitin-associated (UBA) domain. Recent studies have highlighted the critical role of p62 in the development and progression of various malignancies. Overexpression and/or impaired degradation of p62 are linked to the initiation and progression of numerous cancers. While p62 is primarily localized in the cytosol and often considered a cytoplasmic protein, most of the existing literature focuses on its cytoplasmic functions, leaving its nuclear roles less explored. However, an increasing body of research has uncovered p62's involvement in the cellular response to DNA damage. In this review, we summarize the current understanding of p62's molecular functions in malignancies, with particular emphasis on its role in DNA damage repair, highlighting the latest advances in this field.
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Affiliation(s)
- Xiaojuan Yang
- Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xunjie Cao
- Division of Abdominal Tumor Multimodality Treatment, Department of General Surgery, West China Hospital, Sichuan University, Cancer Center, Chengdu, 610041, China
| | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Department of General Surgery, West China Hospital, Sichuan University, Cancer Center, Chengdu, 610041, China.
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Gakinya S, Nzioka AK, Mugo AG, Onyuma T, Ogutu J. Autophagy-related protein LC3β and its association with clinical-pathological characteristics, mismatch repair proteins and survival in colorectal carcinoma. Front Med (Lausanne) 2025; 12:1512127. [PMID: 40018347 PMCID: PMC11865083 DOI: 10.3389/fmed.2025.1512127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/27/2025] [Indexed: 03/01/2025] Open
Abstract
Introduction Autophagy is a metabolic process that serves to maintain cellular homeostasis as well as enable the cell to adapt to metabolic stress. In malignant cells, autophagy has been associated with drug resistance, metastasis and poor outcome. Colorectal carcinoma is a leading cause of cancer morbidity and mortality worldwide. The management and outcome are dependent on the tumor clinical and pathological characteristics. Autophagy is a potential therapeutic target as well as prognostic biomarker given its role in cancer pathogenesis. This study aimed at evaluating the autophagy status of colorectal carcinomas for tumors diagnosed at the Aga Khan University Hospital, Nairobi and establish its association with clinical-pathological characteristics including age, tumor location, tumor grade, tumor pathological stage, tumor nodal stage, tumor budding, tumor-infiltrating lymphocytes (TILs), Mismatch repair protein status (MMR), HER2 status and patient survival. Methods The study assessed the autophagy status of 114 colorectal carcinoma cases using immunohistochemistry for autophagy related protein LC3β. The clinical-pathological characteristics were determined by examining the medical records and evaluation of hematoxylin and eosin-stained slides. HER2 and MMR status were evaluated using immunohistochemistry. The treatment outcome was determined from the patient's records by checking for date of last visit or death. Results and discussion The mean age of patients in our study was 58years. There were more males 61.8% (n = 70) than females 38.6% (n = 44). Most of the patients had high pathological tumor stage of pT3 and pT4. Majority of the tumors showed intermediate tumor budding and weak tumor-infiltrating lymphocytes. The mismatch repair deficiency and HER2 overexpression were found in 14.9% (n = 17) and 2.6% (n = 3) of the cases respectively. LC3β was overexpressed in 36% (n = 41) of the cases and was significantly more common in females (p = 0.013). The LC3β status showed no significant association with age, tumor location, tumor grade, tumor stage, nodal stage, tumor budding, tumor-infiltrating lymphocytes, MMR status, HER2 status or patient survival. Future prospective studies are recommended to further explore the utility of autophagy as a prognostic and predictive biomarker.
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Affiliation(s)
- Samuel Gakinya
- Department of Pathology, Aga Khan University, Nairobi, Kenya
| | - Ancent K. Nzioka
- Department of Pathology, Kenyatta University Teaching, Referral and Research Hospital, Nairobi, Kenya
| | - Alex G. Mugo
- Department of Pathology, Aga Khan University, Nairobi, Kenya
| | - Timothy Onyuma
- Department of Pathology, Kenyatta National Hospital, Nairobi, Kenya
| | - James Ogutu
- Department of Microbiology, Kenyatta University, Nairobi, Kenya
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Niu X, You Q, Hou K, Tian Y, Wei P, Zhu Y, Gao B, Ashrafizadeh M, Aref AR, Kalbasi A, Cañadas I, Sethi G, Tergaonkar V, Wang L, Lin Y, Kang D, Klionsky DJ. Autophagy in cancer development, immune evasion, and drug resistance. Drug Resist Updat 2025; 78:101170. [PMID: 39603146 DOI: 10.1016/j.drup.2024.101170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 10/22/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024]
Abstract
Macroautophagy/autophagy is a highly conserved evolutionary mechanism involving lysosomes for the degradation of cytoplasmic components including organelles. The constitutive, basal level of autophagy is fundamental for preserving cellular homeostasis; however, alterations in autophagy can cause disease pathogenesis, including cancer. The role of autophagy in cancer is particularly complicated, since this process acts both as a tumor suppressor in precancerous stages but facilitates tumor progression during carcinogenesis and later stages of cancer progression. This shift between anti-tumor and pro-tumor roles may be influenced by genetic and environmental factors modulating key pathways such as those involving autophagy-related proteins, the PI3K-AKT-MTOR axis, and AMPK, which often show dysregulation in tumors. Autophagy regulates various cellular functions, including metabolism of glucose, glutamine, and lipids, cell proliferation, metastasis, and several types of cell death (apoptosis, ferroptosis, necroptosis and immunogenic cell death). These multifaceted roles demonstrate the potential of autophagy to affect DNA damage repair, cell death pathways, proliferation and survival, which are critical in determining cancer cells' response to chemotherapy. Therefore, targeting autophagy pathways presents a promising strategy to combat chemoresistance, as one of the major reasons for the failure in cancer patient treatment. Furthermore, autophagy modulates immune evasion and the function of immune cells such as T cells and dendritic cells, influencing the tumor microenvironment and cancer's biological behavior. However, the therapeutic targeting of autophagy is complex due to its dual role in promoting survival and inducing cell death in cancer cells, highlighting the need for strategies that consider both the beneficial and detrimental effects of autophagy modulation in cancer therapy. Hence, both inducers and inhibitors of autophagy have been introduced for the treatment of cancer. This review emphasizes the intricate interplay between autophagy, tumor biology, and immune responses, offering insights into potential therapeutic approaches that deploy autophagy in the cancer suppression.
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Affiliation(s)
- Xuegang Niu
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Qi You
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Kaijian Hou
- School of Public Health（Long Hu people hospital), Shantou University, Shantou, 515000, Guangdong, China
| | - Yu Tian
- School of Public Health, Benedictine University, Lisle, IL 60532, USA
| | - Penghui Wei
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Yang Zhu
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Bin Gao
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Amir Reza Aref
- VitroVision Department, DeepkinetiX, Inc, Boston, MA, USA
| | - Alireza Kalbasi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Israel Cañadas
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Gautam Sethi
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A⁎STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Lingzhi Wang
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore
| | - Yuanxiang Lin
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
| | - Dezhi Kang
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
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Cao Z, Tian K, Ran Y, Zhou H, Zhou L, Ding Y, Tang X. Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment. Front Immunol 2024; 15:1506426. [PMID: 39650649 PMCID: PMC11621085 DOI: 10.3389/fimmu.2024.1506426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/01/2024] [Indexed: 12/11/2024] Open
Abstract
The significant identification of Beclin-1's function in regulating autophagy flow signified a significant progression in our understanding of cellular operations. Beclin-1 acts as a scaffold for forming the PI3KC3 complex, controlling autophagy and cellular trafficking processes in a complicated way. This intricate protein has garnered considerable attention due to its substantial impact on the development of tumors. Strong evidence indicates Beclin-1 plays a critical role in controlling autophagy in various human cancer types and its intricate connection with apoptosis and ferroptosis. The potential of Beclin-1 as a viable target for cancer therapy is highlighted by its associations with key autophagy regulators such as AMPK, mTOR, and ATGs. Beclin-1 controls the growth and dissemination of tumors by autophagy. It also affects how tumors react to therapies such as chemotherapy and radiation therapy. The role of Beclin-1 in autophagy can influence apoptosis, depending on whether it supports cell survival or leads to cell death. Beclin-1 plays a crucial role in ferroptosis by increasing ATG5 levels, which in turn promotes autophagy-triggered ferroptosis. Finally, we analyzed the possible function of Beclin-1 in tumor immunology and drug sensitivity in cancers. In general, Beclin-1 has a significant impact on regulating autophagy, offering various potentials for medical intervention and altering our understanding of cancer biology.
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Affiliation(s)
- Zhumin Cao
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Ke Tian
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yincheng Ran
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Haonan Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Lei Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yana Ding
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
| | - Xiaowei Tang
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
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9
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Kundu M, Das S, Dey A, Mandal M. Dual perspective on autophagy in glioma: Detangling the dichotomous mechanisms of signaling pathways for therapeutic insights. Biochim Biophys Acta Rev Cancer 2024; 1879:189168. [PMID: 39121913 DOI: 10.1016/j.bbcan.2024.189168] [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: 04/16/2024] [Revised: 06/25/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Autophagy is a normal physiological process that aids the recycling of cellular nutrients, assisting the cells to cope with stressed conditions. However, autophagy's effect on cancer, including glioma, is uncertain and involves complicated molecular mechanisms. Several contradictory reports indicate that autophagy may promote or suppress glioma growth and progression. Autophagy inhibitors potentiate the efficacy of chemotherapy or radiation therapy in glioma. Numerous compounds stimulate autophagy to cause glioma cell death. Autophagy is also involved in the therapeutic resistance of glioma. This review article aims to detangle the complicated molecular mechanism of autophagy to provide a better perception of the two-sided role of autophagy in glioma and its therapeutic implications. The protein and epigenetic modulators of the cytoprotective and cytotoxic role of autophagy are described in this article. Moreover, several signaling pathways are associated with autophagy and its effects on glioma. We have reviewed the molecular pathways and highlighted the signaling axis involved in cytoprotective and cytotoxic autophagy. Additionally, this article discusses the role of autophagy in therapeutic resistance, including glioma stem cell maintenance and tumor microenvironment regulation. It also summarizes several investigations on the anti-glioma effects of autophagy modulators to understand the associated mechanisms and provide insights regarding its therapeutic implications.
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Affiliation(s)
- Moumita Kundu
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India; Center for Multidisciplinary Research & Innovations, Brainware University, Barasat, India; Department of Pharmaceutical Technology, Brainware University, Barasat, India.
| | - Subhayan Das
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India; Department of Allied Health Sciences, Brainware University, Barasat, India
| | - Ankita Dey
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India.
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10
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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11
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [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: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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12
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Zhou XC, Wang DX, Zhang CY, Yang YJ, Zhao RB, Liu SY, Ni GX. Exercise promotes osteogenic differentiation by activating the long non-coding RNA H19/microRNA-149 axis. World J Orthop 2024; 15:363-378. [PMID: 38680671 PMCID: PMC11045468 DOI: 10.5312/wjo.v15.i4.363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/04/2024] [Accepted: 03/19/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Regular physical activity during childhood and adolescence is beneficial to bone development, as evidenced by the ability to increase bone density and peak bone mass by promoting bone formation. AIM To investigate the effects of exercise on bone formation in growing mice and to investigate the underlying mechanisms. METHODS 20 growing mice were randomly divided into two groups: Con group (control group, n = 10) and Ex group (treadmill exercise group, n = 10). Hematoxylin-eosin staining, immunohistochemistry, and micro-CT scanning were used to assess the bone formation-related indexes of the mouse femur. Bioinformatics analysis was used to find potential miRNAs targets of long non-coding RNA H19 (lncRNA H19). RT-qPCR and Western Blot were used to confirm potential miRNA target genes of lncRNA H19 and the role of lncRNA H19 in promoting osteogenic differentiation. RESULTS Compared with the Con group, the expression of bone morphogenetic protein 2 was also significantly increased. The micro-CT results showed that 8 wk moderate-intensity treadmill exercise significantly increased bone mineral density, bone volume fraction, and the number of trabeculae, and decreased trabecular segregation in the femur of mice. Inhibition of lncRNA H19 significantly upregulated the expression of miR-149 and suppressed the expression of markers of osteogenic differentiation. In addition, knockdown of lncRNA H19 significantly downregulated the expression of autophagy markers, which is consistent with the results of autophagy-related protein changes detected in mouse femurs by immunofluorescence. CONCLUSION Appropriate treadmill exercise can effectively stimulate bone formation and promote the increase of bone density and bone volume in growing mice, thus enhancing the peak bone mass of mice. The lncRNA H19/miR-149 axis plays an important regulatory role in osteogenic differentiation.
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Affiliation(s)
- Xu-Chang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Dong-Xue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Chun-Yu Zhang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Ya-Jing Yang
- Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Ruo-Bing Zhao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Sheng-Yao Liu
- Department of Spinal Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Guo-Xin Ni
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
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13
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Schmid M, Fischer P, Engl M, Widder J, Kerschbaum-Gruber S, Slade D. The interplay between autophagy and cGAS-STING signaling and its implications for cancer. Front Immunol 2024; 15:1356369. [PMID: 38660307 PMCID: PMC11039819 DOI: 10.3389/fimmu.2024.1356369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Autophagy is an intracellular process that targets various cargos for degradation, including members of the cGAS-STING signaling cascade. cGAS-STING senses cytosolic double-stranded DNA and triggers an innate immune response through type I interferons. Emerging evidence suggests that autophagy plays a crucial role in regulating and fine-tuning cGAS-STING signaling. Reciprocally, cGAS-STING pathway members can actively induce canonical as well as various non-canonical forms of autophagy, establishing a regulatory network of feedback mechanisms that alter both the cGAS-STING and the autophagic pathway. The crosstalk between autophagy and the cGAS-STING pathway impacts a wide variety of cellular processes such as protection against pathogenic infections as well as signaling in neurodegenerative disease, autoinflammatory disease and cancer. Here we provide a comprehensive overview of the mechanisms involved in autophagy and cGAS-STING signaling, with a specific focus on the interactions between the two pathways and their importance for cancer.
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Affiliation(s)
- Maximilian Schmid
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- MedAustron Ion Therapy Center, Wiener Neustadt, Austria
- Department of Medical Biochemistry, Medical University of Vienna, Max Perutz Labs, Vienna Biocenter, Vienna, Austria
| | - Patrick Fischer
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- MedAustron Ion Therapy Center, Wiener Neustadt, Austria
- Department of Medical Biochemistry, Medical University of Vienna, Max Perutz Labs, Vienna Biocenter, Vienna, Austria
| | - Magdalena Engl
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Department of Medical Biochemistry, Medical University of Vienna, Max Perutz Labs, Vienna Biocenter, Vienna, Austria
- Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Joachim Widder
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Sylvia Kerschbaum-Gruber
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- MedAustron Ion Therapy Center, Wiener Neustadt, Austria
| | - Dea Slade
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- MedAustron Ion Therapy Center, Wiener Neustadt, Austria
- Department of Medical Biochemistry, Medical University of Vienna, Max Perutz Labs, Vienna Biocenter, Vienna, Austria
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14
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Xiao N, Xie Z, He Z, Xu Y, Zhen S, Wei Y, Zhang X, Shen J, Wang J, Tian Y, Zuo J, Peng J, Li Z. Pathogenesis of gout: Exploring more therapeutic target. Int J Rheum Dis 2024; 27:e15147. [PMID: 38644732 DOI: 10.1111/1756-185x.15147] [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: 12/02/2023] [Revised: 03/28/2024] [Accepted: 03/30/2024] [Indexed: 04/23/2024]
Abstract
Gout is a chronic metabolic and immune disease, and its specific pathogenesis is still unclear. When the serum uric acid exceeds its saturation in the blood or tissue fluid, it is converted to monosodium urate crystals, which lead to acute arthritis of varying degrees, urinary stones, or irreversible peripheral joint damage, and in severe cases, impairment of vital organ function. Gout flare is a clinically significant state of acute inflammation in gout. The current treatment is mostly anti-inflammatory analgesics, which have numerous side effects with limited treatment methods. Gout pathogenesis involves many aspects. Therefore, exploring gout pathogenesis from multiple perspectives is conducive to identifying more therapeutic targets and providing safer and more effective alternative treatment options for patients with gout flare. Thus, this article is of great significance for further exploring the pathogenesis of gout. The author summarizes the pathogenesis of gout from four aspects: signaling pathways, inflammatory factors, intestinal flora, and programmed cell death, focusing on exploring more new therapeutic targets.
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Affiliation(s)
- Niqin Xiao
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Zhaohu Xie
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, China
| | - Zhiyan He
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Yundong Xu
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Shuyu Zhen
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Yuanyuan Wei
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Xiaoyu Zhang
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Jiayan Shen
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Jian Wang
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Yadan Tian
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Jinlian Zuo
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China
| | - Jiangyun Peng
- The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Zhaofu Li
- Yunnan University of Chinese Medicine, Kunming, China
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15
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Cui Z, Cong M, Yin S, Li Y, Ye Y, Liu X, Tang J. Role of protein degradation systems in colorectal cancer. Cell Death Discov 2024; 10:141. [PMID: 38485957 PMCID: PMC10940631 DOI: 10.1038/s41420-023-01781-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 03/18/2024] Open
Abstract
Protein degradation is essential for maintaining protein homeostasis. The ubiquitin‒proteasome system (UPS) and autophagy-lysosome system are the two primary pathways responsible for protein degradation and directly related to cell survival. In malignant tumors, the UPS plays a critical role in managing the excessive protein load caused by cancer cells hyperproliferation. In this review, we provide a comprehensive overview of the dual roles played by the UPS and autolysosome system in colorectal cancer (CRC), elucidating their impact on the initiation and progression of this disease while also highlighting their compensatory relationship. Simultaneously targeting both protein degradation pathways offers new promise for enhancing treatment efficacy against CRC. Additionally, apoptosis is closely linked to ubiquitination and autophagy, and caspases degrade proteins. A thorough comprehension of the interplay between various protein degradation pathways is highly important for clarifying the mechanism underlying the onset and progression of CRC.
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Affiliation(s)
- Zihan Cui
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Mingqi Cong
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Shengjie Yin
- Department of Oncology, Chifeng City Hospital, Chifeng, 024000, China
| | - Yuqi Li
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Yuguang Ye
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
| | - Xi Liu
- Cardiovascular Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China.
| | - Jing Tang
- Department of Pathology, Harbin Medical University, Harbin, 150081, China.
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de Oliveira Silva N, de Lima LVA, de Oliveira LM, da Silva MF, de Aguiar AP, Semprebon SC, Favaron PO, Lepri SR, Felicidade I, Mantovani MS. Cellular and molecular antiproliferative effects in 2D monolayer and 3D-cultivated HT-29 cells treated with zerumbone. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1561-1573. [PMID: 37672080 DOI: 10.1007/s00210-023-02701-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/29/2023] [Indexed: 09/07/2023]
Abstract
Zerumbone (ZER) is a phytochemical isolated from plants of the Zingiberaceae family. Numerous studies have demonstrated its diverse pharmacological properties, particularly its potent antitumorigenic activity. This study aimed to assess the antiproliferative effects of ZER on HT-29 cells cultivated in both two-dimensional (2D) monolayer and three-dimensional (3D) spheroid culture systems. The evaluation of growth (size), cell death, and cell cycle arrest in 3D spheroid HT-29 cells was correlated with mRNA expression data. Treatment of 2D cells revealed that ZER exhibited cytotoxicity at concentrations above 30 µM, and an IC50 of 83.54 µM (24-h post-ZER treatment) effectively suppressed cell migration. In the 3D model, ZER induced an increase in spheroid volume over a 72-h period attributed to disaggregation and reconfiguration of characteristic zones. Analysis of cell death demonstrated a significant rise in apoptotic cells after 24 h of ZER treatment, along with cell cycle arrest in the G1 phase. Furthermore, ZER treatment resulted in alterations in mRNA expression, affecting key signaling pathways involved in cell death (BCL2 and BBC3), endoplasmic reticulum stress (ERN1), DNA damage (GADD45A), cell cycle regulation (CDKN1A, NFKB1, MYC, and TP53), and autophagy (BECN1 and SQSTM1). These findings suggested that ZER holds promise as a potential candidate for the development of novel anticancer agents that can modulate crucial cell signaling pathways. Additionally, the use of the 3D culture system proved to be a valuable tool in our investigation.
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Affiliation(s)
- Nayane de Oliveira Silva
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Luan Vitor Alves de Lima
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Liana Martins de Oliveira
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Matheus Felipe da Silva
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Amanda Passuello de Aguiar
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Simone Cristine Semprebon
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Phelipe Oliveira Favaron
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Sandra Regina Lepri
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Ingrid Felicidade
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Mario Sergio Mantovani
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil.
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17
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Xu Y, Zhu C, Zhu C, Peng L, Ji D, Wu Q, Bai P, Bai Z, Da M. SQSTM1/p62 promotes the progression of gastric cancer through epithelial-mesenchymal transition. Heliyon 2024; 10:e24409. [PMID: 38322900 PMCID: PMC10844054 DOI: 10.1016/j.heliyon.2024.e24409] [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: 09/02/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
Background SQSTM1/p62 is an autophagy-related receptor protein that participates in regulating tumorigenesis and multiple signaling pathways. Gastric cancer (GC) is a common tumor in the digestive tract and continues to pose a significant threat to human health. Therefore, this study aims to investigate the impact of p62 on gastric cancer. Methods Immunohistochemistry and Western blotting were employed to assess the expression level of the p62 protein in gastric cancer tissues and its correlation with prognosis. Subsequently, in vitro cell experiments were conducted to determine the role of p62 in gastric cancer cell proliferation, migration, and metastasis. Result The expression of p62 in gastric cancer tissues was significantly higher than in normal tissues. The expression of p62 was positively correlated with poor prognosis in gastric cancer patients. In vitro cell experiments indicated that p62 promotes gastric cancer cell proliferation and migration. Mechanistically, elevated p62 expression induced epithelial-mesenchymal transition (EMT), leading to upregulation of E-cadherin and downregulation of N-cadherin and vimentin. Conclusion This study provides novel and robust evidence for the mechanism by which elevated p62 expression promotes the progression of gastric cancer. It offers promising therapeutic targets for anti-tumor treatment strategies in gastric cancer patients.
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Affiliation(s)
- Yan Xu
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou,730000, China
| | - Ciba Zhu
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou,730000, China
| | - Chenglou Zhu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Lingzhi Peng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Dandan Ji
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou,730000, China
| | - Qiong Wu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Pengwei Bai
- Clinical Medical College of Ningxia Medical University, 750000, Yinchuan, China
| | - Zhaozhao Bai
- Clinical Medical College of Ningxia Medical University, 750000, Yinchuan, China
| | - Mingxu Da
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, 730000, China
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18
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Hill RM, Fok M, Grundy G, Parsons JL, Rocha S. The role of autophagy in hypoxia-induced radioresistance. Radiother Oncol 2023; 189:109951. [PMID: 37838322 PMCID: PMC11046710 DOI: 10.1016/j.radonc.2023.109951] [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: 06/21/2023] [Revised: 09/25/2023] [Accepted: 09/29/2023] [Indexed: 10/16/2023]
Abstract
Radiotherapy is a widely used treatment modality against cancer, and although survival rates are increasing, radioresistant properties of tumours remain a significant barrier for curative treatment. Tumour hypoxia is one of the main contributors to radioresistance and is common in most solid tumours. Hypoxia is responsible for many molecular changes within the cell which helps tumours to survive under such challenging conditions. These hypoxia-induced molecular changes are predominantly coordinated by the hypoxia inducible factor (HIF) and have been linked with the ability to confer resistance to radiation-induced cell death. To overcome this obstacle research has been directed towards autophagy, a cellular process involved in self degradation and recycling of macromolecules, as HIF plays a large role in its coordination under hypoxic conditions. The role that autophagy has following radiotherapy treatment is conflicted with evidence of both cytoprotective and cytotoxic effects. This literature review aims to explore the intricate relationship between radiotherapy, hypoxia, and autophagy in the context of cancer treatment. It provides valuable insights into the potential of targeting autophagy as a therapeutic strategy to improve the response of hypoxic tumours to radiotherapy.
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Affiliation(s)
- Rhianna Mae Hill
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, L7 8TX, UK
| | - Matthew Fok
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, L7 8TX, UK
| | - Gabrielle Grundy
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, L7 8TX, UK
| | - Jason Luke Parsons
- Institute of Cancer and Genomic Sciences, University of Birmingham, B15 2TT, UK
| | - Sonia Rocha
- Department of Biochemistry and Systems Biology, University of Liverpool, L69 7ZB, UK.
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19
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Zhang X, Li F, Li R, Zhao N, Liu D, Xu Y, Wang L, Wang D, Zhao R. B7 Induces Apoptosis in Colorectal Cancer Cells by Regulating the Expression of Caspase-3 and Inhibits Autophagy. Onco Targets Ther 2023; 16:867-883. [PMID: 37915320 PMCID: PMC10617530 DOI: 10.2147/ott.s429128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/18/2023] [Indexed: 11/03/2023] Open
Abstract
Purpose Heterocyclic compounds are organic compounds with heterocyclic structures, which are common in drug molecules. They include pyrazines with diverse functions, including anti-cancer, antimicrobial, antidiabetic, and anticholinergic activities. In this study a new small molecular compound B7 based on tetrazolium substituted pyrazine was synthesized and its effect on the progression of colorectal cancer (CRC) and its potential mechanism were investigated. Methods We synthesized a series of tetrazolium-substituted pyrazine compounds by chemoenzymatic method. NCM460 (Human), HCT116 (Human), SW480 (Human) cell lines were selected to analyse the inhibitory effect of B7 on CRC by CCK-8, apoptosis, cell migration and invasion, qPCR, Western blotting, molecular docking, immunofluorescence. Moreover, a CRC xenograft model of mice was used to analyzed the role of B7 in vivo. Results Among these compounds, 3-methyl-5je-6-bis (1H-tetrazole-5-yl) pyrazine-2-carboxylic acid (B7) inhibited CRC cell proliferation and induced apoptosis. The expression of Caspase-3 was increased after B7 treatment. In addition, the mitochondria abnormalities was observed in B7 group due to decrease the expression of Beclin-1. In addition, B7 inhibited the migration and invasion in CRC cells. Finally, the results showed that B7 had anti-tumor activity in CRC xenograft model of mice. Conclusion In summary, compound B7 was synthesized efficiently using tetrazolium-substituted pyrazine via a chemoenzymatic method. Moreover, B7 have ability to regulate the expression of Caspase-3 which induced apoptosis in CRC cells. In addition, decreased Beclin-1 expression after B7 treatment, indicating inhibited autophagy. This study showed that B7 effectively induced apoptosis and inhibited autophagy in CRC cells.
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Affiliation(s)
- Xinyi Zhang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, 130062, People’s Republic of China
| | - Fengxi Li
- Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130023, People’s Republic of China
| | - Rong Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, 130062, People’s Republic of China
| | - Nan Zhao
- Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130023, People’s Republic of China
| | - Dianfeng Liu
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, 130062, People’s Republic of China
| | - Yuelin Xu
- Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130023, People’s Republic of China
| | - Lei Wang
- Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130023, People’s Republic of China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, 130062, People’s Republic of China
| | - Ruihong Zhao
- Department of Gastroenterology Endoscopy Center, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China
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20
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Shen N, Wang L, Wu J, Chen X, Hu F, Su Y. Meta‑analysis of the autophagy‑associated protein LC3 as a prognostic marker in colorectal cancer. Exp Ther Med 2023; 26:492. [PMID: 37753301 PMCID: PMC10518644 DOI: 10.3892/etm.2023.12191] [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: 01/09/2023] [Accepted: 08/02/2023] [Indexed: 09/28/2023] Open
Abstract
Microtubule-associated protein 1 light chain 3 (LC3) is an autophagy-associated gene, which is involved in the progression of a number of human malignancies. Such as Breast Cancer, Liver Cancer, and Lung Cancer. However, the role of LC3 in colorectal cancer (CC) remains to be fully elucidated. Therefore, the prognostic role of LC3 expression in CC was evaluated in the present study, with an emphasis on the clinicopathology and prognosis. Expression of LC3 in CC was examined using PubMed, Cochrane Library, Excerpta Medica Database, China Knowledge Infrastructure and Wanfang Data. Newcastle-Ottawa scale was used to screen the literature quality, and RevMan 5.4 and STATA 14.0 were used for the meta-analysis. A total of 1,689 patients from 10 studies were included in the present meta-analysis. The findings of the present study suggested that increased LC3 expression levels were associated with histological grade [odds ratio (OR)=0.91, 95% confidence interval (CI) (0.47, 1.77), P<0.001] and TNM stage [OR=0.91, 95% CI (0.47, 1.77), P<0.001], but were not associated with sex [OR=1.14, 95% CI (0.90, 1.51)], age [OR=0.89, 95% CI (0.67, 1.20)], tumor size [OR=0.78, 95% CI (0.30, 2.34)], histological grade [OR=0.82, 95% CI (0.43, 1.95)] and lymph node metastasis [OR=2.05, 95% CI (1.19, 3.60)] in CC. In addition, the increased expression of LC3 was revealed to be a prognostic factor for the overall survival of patients with CC. In conclusion, the autophagy-associated protein LC3 may be a prognostic indicator of human CC.
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Affiliation(s)
- Ning Shen
- Department of Oncology, Zhangqiu People's Hospital, Jinan, Shandong 250200, P.R. China
| | - Lijuan Wang
- Blood Purification Center, Suzhou Science and Technology Town Hospital, Suzhou, Jiangsu 215153, P.R. China
| | - Jingjing Wu
- Department of Oncology, Zhangqiu People's Hospital, Jinan, Shandong 250200, P.R. China
| | - Xuefang Chen
- Blood Purification Center, Suzhou Science and Technology Town Hospital, Suzhou, Jiangsu 215153, P.R. China
| | - Fengchao Hu
- Department of Oncology, Zhangqiu People's Hospital, Jinan, Shandong 250200, P.R. China
| | - Yi Su
- Quality Management Office, Zhangqiu People's Hospital, Jinan, Shandong 250200, P.R. China
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21
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Alherz FA, Elekhnawy E, Selim HM, El-Masry TA, El-Kadem AH, Hussein IA, Negm WA. Protective Role of Betulinic Acid against Cisplatin-Induced Nephrotoxicity and Its Antibacterial Potential toward Uropathogenic Bacteria. Pharmaceuticals (Basel) 2023; 16:1180. [PMID: 37631096 PMCID: PMC10458273 DOI: 10.3390/ph16081180] [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: 06/19/2023] [Revised: 08/01/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Acute kidney injury (AKI) is one of the major side effects of cisplatin, a remarkable anticancer agent. Therefore, there is a growing need to find an agent that could mitigate cisplatin-induced nephrotoxicity. Betulinic acid (BA) is a natural compound isolated from Silene succulenta Forssk for the first time, with miraculous biological activities and no reports of its effect on the nephrotoxicity induced by cisplatin. Mice received BA orally with doses of 30 and 50 mg/kg before the intraperitoneal injection of cisplatin. Betulinic acid was found to decrease serum levels of creatinine and tissue levels of NGAL and kidney injury molecule (KIM-1) and improve the histological changes in the kidney. In addition, BA decreased the oxidative stress marker malondialdehyde (MDA), increased superoxide dismutase (SOD) antioxidative activity and suppressed the intensity of IL-1B and NFкB immuno-staining. Interestingly, betulinic acid enhanced autophagy by increasing beclin 1, ATG5, and LC3II and decreasing p62 expressions. Thus, our findings suggest betulinic acid as a potential agent that may protect from acute kidney injury by targeting inflammation, oxidative stress, and autophagy processes. Novel drugs are needed to combat the spreading of multidrug resistance between pathogenic bacteria, especially uropathogenic isolates. So, we elucidated the antibacterial properties of BA on Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Betulinic acid had minimum inhibitory concentration values (128 to 512 µg/mL). In addition, it adversely affected the membrane integrity of the tested isolates. Accordingly, betulinic acid should be clinically investigated in the future for urinary tract diseases.
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Affiliation(s)
- Fatemah A Alherz
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Engy Elekhnawy
- Pharmaceutical Microbiology Department, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Hend Mostafa Selim
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Thanaa A El-Masry
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Aya H El-Kadem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Ismail A Hussein
- Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
| | - Walaa A Negm
- Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
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22
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Liu W, Hu C, Zhang B, Li M, Deng F, Zhao S. Exosomal microRNA-342-5p secreted from adipose-derived mesenchymal stem cells mitigates acute kidney injury in sepsis mice by inhibiting TLR9. Biol Proced Online 2023; 25:10. [PMID: 37085762 PMCID: PMC10120132 DOI: 10.1186/s12575-023-00198-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 04/11/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUND Sepsis-related acute kidney injury (AKI) is an inflammatory disease associated with extremely high mortality and health burden. This study explored the possibility of exosomes secreted by adipose-derived mesenchymal stem cells (AMSCs) serving as a carrier for microRNA (miR)-342-5p to alleviate sepsis-related AKI and investigated the possible mechanism. METHODS Serum was obtained from 30 patients with sepsis-associated AKI and 30 healthy volunteers for the measurement of miR-342-5p, blood urea nitrogen (BUN), and serum creatinine (SCr) levels. For in vitro experiments, AMSCs were transfected with LV-miR-342-5p or LV-miR-67 to acquire miR-342-5p-modified AMSCs and miR-67-modified AMSCs, from which the exosomes (AMSC-Exo-342 and AMSC-Exo-67) were isolated. The human renal proximal tubular epithelial cell line HK-2 was induced by lipopolysaccharide (LPS) to construct a cellular model of sepsis. The expression of Toll-like receptor 9 (TLR9) was also detected in AKI cells and mouse models. The interaction between miR-342-5p and TLR9 was predicted by dual luciferase reporter gene assay. RESULTS Detection on clinical serum samples showed that BUN, SCr, and TLR9 were elevated and miR-342-5p level was suppressed in the serum of patients with sepsis-associated AKI. Transfection with LV-miR-342-5p reinforced miR-342-5p expression in AMSCs and AMSC-secreted exosomes. miR-342-5p negatively targeted TLR9. LPS treatment enhanced TLR9 expression, reduced miR-342-5p levels, suppressed autophagy, and increased inflammation in HK-2 cells, while the opposite trends were observed in LPS-induced HK-2 cells exposed to AMSC-Exo-342, Rapa, miR-342-5p mimic, or si-TLR9. Additionally, the effects of AMSC-Exo-342 on autophagy and inflammation in LPS-induced cells could be weakened by 3-MA or pcDNA3.1-TLR9 treatment. Injection of AMSC-Exo-342 enhanced autophagy, mitigated kidney injury, suppressed inflammation, and reduced BUN and SCr levels in sepsis-related AKI mouse models. CONCLUSION miR-342-5p transferred by exosomes from miR-342-5p-modified AMSCs ameliorated AKI by inhibiting TLR9 to accelerate autophagy.
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Affiliation(s)
- Wei Liu
- Department of Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Chenghuan Hu
- Department of Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Buyao Zhang
- Department of Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Mingxia Li
- Department of Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Fuxing Deng
- Department of Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Shuangping Zhao
- Department of Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
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23
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Transcription of Autophagy Associated Gene Expression as Possible Predictors of a Colorectal Cancer Prognosis. Biomedicines 2023; 11:biomedicines11020418. [PMID: 36830954 PMCID: PMC9952998 DOI: 10.3390/biomedicines11020418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/04/2023] Open
Abstract
(1) Background: Autophagy plays a dual role in oncogenesis-it contributes to the growth of the tumor and can inhibit its development. The aim of this study was to assess changes in the transcriptional activity of LAMP-2, BECN1, PINK1, and FOXO1 genes involved in the autophagy process in histopathologically confirmed adenocarcinoma sections of colorectal cancer: (2) Methods: A gene expression profile analysis was performed using HG-U133A and the RT-qPCR reaction. The transcriptional activity of genes was compared in sections of colorectal cancer in the four clinical stages (CSI-CSIV) concerning the control group; (3) Results: In CSI, the transcriptional activity of the PINK1 gene is highest; in CS II, the LAMP-2 gene is highest, while FOXO1 increases gradually from CSI reaching a maximum in CSIII. There is no BECN1 gene expression in colorectal cancer cells; (4) Conclusions: The observed differences in the mRNA concentration profile of autophagy-related genes in colon cancer specimens may indicate the role of autophagy in the pathogenesis of this cancer. Genes involved in autophagy may be diagnostic tools for colorectal cancer screening and personalized therapy in the future.
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24
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Gamage CDB, Kim JH, Yang Y, Taş İ, Park SY, Zhou R, Pulat S, Varlı M, Hur JS, Nam SJ, Kim H. Libertellenone T, a Novel Compound Isolated from Endolichenic Fungus, Induces G2/M Phase Arrest, Apoptosis, and Autophagy by Activating the ROS/JNK Pathway in Colorectal Cancer Cells. Cancers (Basel) 2023; 15:cancers15020489. [PMID: 36672439 PMCID: PMC9857212 DOI: 10.3390/cancers15020489] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most deadly type of cancer in the world and continuous investigations are required to discover novel therapeutics for CRC. Induction of apoptosis is one of the promising strategies to inhibit cancers. Here, we have identified a novel compound, Libertellenone T (B), isolated from crude extracts of the endolichenic fungus from Pseudoplectania sp. (EL000327) and investigated the mechanism of action. CRC cells treated by B were subjected to apoptosis detection assays, immunofluorescence imaging, and molecular analyses such as immunoblotting and QRT-PCR. Our findings revealed that B induced CRC cell death via multiple mechanisms including G2/M phase arrest caused by microtubule stabilization and caspase-dependent apoptosis. Further studies revealed that B induced the generation of reactive oxygen species (ROS) attributed to activating the JNK signaling pathway by which apoptosis and autophagy was induced in Caco2 cells. Moreover, B exhibited good synergistic effects when combined with the well-known anticancer drug, 5-FU, and another cytotoxic novel compound D, which was isolated from the same crude extract of EL000327. Overall, Libertellenone T induces G2/M phase arrest, apoptosis, and autophagy via activating the ROS/JNK pathway in CRC. Thus, B may be a potential anticancer therapeutic against CRC that is suitable for clinical applications.
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Affiliation(s)
- Chathurika D. B. Gamage
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Jeong-Hyeon Kim
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yi Yang
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - İsa Taş
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - So-Yeon Park
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Rui Zhou
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Sultan Pulat
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Mücahit Varlı
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Jae-Seoun Hur
- Korean Lichen Research Institute, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Sang-Jip Nam
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea
- Correspondence: (S.-J.N.); (H.K.)
| | - Hangun Kim
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
- Correspondence: (S.-J.N.); (H.K.)
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25
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Nishizawa N, Kurasaka C, Ogino Y, Sato A. Regulation of 5-fluorodeoxyuridine monophosphate-thymidylate synthase ternary complex levels by autophagy confers resistance to 5-fluorouracil. FASEB Bioadv 2023; 5:43-51. [PMID: 36643896 PMCID: PMC9832531 DOI: 10.1096/fba.2022-00099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
5-Fluorouracil (5-FU) is a cornerstone drug used to treat colorectal cancer (CRC). However, the prolonged exposure of CRC cells to 5-FU results in acquired resistance. We have previously demonstrated that levels of the 5-fluorodeoxyuridylate (FdUMP) covalent complex with thymidylate synthase (FdUMP-TS) and free-TS (native enzyme) are higher in 5-FU-resistant CRC cells than in the parental cell line (HCT116). Accordingly, resistant cells may have an efficient system for trapping and removing FdUMP-TS, thus imparting resistance. In this study, using a model of 5-FU-resistant CRC cells generated by repeated exposure, the role of autophagy in the elimination of FdUMP-TS in resistant cells was investigated. The resistant cells showed greater sensitivity to autophagy inhibitors than that of parental cells. Autophagy inhibition increased 5-FU cytotoxicity more substantially in resistant cells than in parental cells. Furthermore, autophagy inhibition increased FdUMP-TS protein accumulation in resistant cells. Our findings suggest that resistance to 5-FU is mediated by autophagy as a system to eliminate FdUMP-TS and may guide the use and optimization of combination therapies involving autophagy inhibitors.
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Affiliation(s)
- Nana Nishizawa
- Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
| | - Chinatsu Kurasaka
- Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
- Present address:
Kowa Company Ltd.Nihonbashi‐HonchoTokyoJapan
| | - Yoko Ogino
- Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
- Present address:
Department of Gene Regulation, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
| | - Akira Sato
- Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
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Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy. Cells 2022; 11:cells11233773. [PMID: 36497032 PMCID: PMC9738281 DOI: 10.3390/cells11233773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment.
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Hu D, Huo Y, Xue Y, Feng H, Sun W, Wang H, Wu J, Wang X. Clinical application of autophagy proteins as prognostic biomarkers in colorectal cancer: a meta-analysis. Future Oncol 2022; 18:3537-3549. [PMID: 36189673 DOI: 10.2217/fon-2022-0458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim: To evaluate the prognostic value of autophagy proteins in colorectal cancer (CRC). Methods: Six potential autophagy proteins were analyzed (Beclin-1, LC3A, LC3B, ULK1, ATG10 and p62). Hazard ratios (HRs) and 95% CIs for overall survival (OS) of CRC patients were calculated. Results: A total of 20 studies were included. High expression of LC3B and p62 was associated with favorable OS (HR: 0.56, 95% CI: 0.40-0.80; HR: 0.76, 95% CI: 0.61-0.96), whereas high expression of Beclin-1 (HR: 1.47, 95% CI: 1.05-2.06) and ULK1 (HR: 1.92. 95% CI: 1.05-3.53) might predict worse OS in CRC patients. Conclusion: Beclin-1, LC3B and p62 might act as promising prognostic biomarkers for CRC. High LC3 and p62 expression can be reliable tools for metastasis prediction.
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Affiliation(s)
- Dongqing Hu
- Department of Healthcare Security Management, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China.,Tibetan Medicine Administration of Tibet Autonomous Region, Chengguan District, Lhasa, China.,Department of Digestive Endoscopy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 42, Wenhua West Road, Jinan, Shandong Province, 250011, China
| | - Yanming Huo
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Ye Xue
- Department of Digestive Endoscopy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 42, Wenhua West Road, Jinan, Shandong Province, 250011, China
| | - Haixia Feng
- Department of Infection Management, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 42, Wenhua West Road, Jinan, Shandong Province, 250011, China
| | - Wei Sun
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Huiqi Wang
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Jing Wu
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Xiaoyan Wang
- Department of Healthcare Security Management, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China.,Tibetan Medicine Administration of Tibet Autonomous Region, Chengguan District, Lhasa, China
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Mahgoub E, Taneera J, Sulaiman N, Saber-Ayad M. The role of autophagy in colorectal cancer: Impact on pathogenesis and implications in therapy. Front Med (Lausanne) 2022; 9:959348. [PMID: 36160153 PMCID: PMC9490268 DOI: 10.3389/fmed.2022.959348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/11/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is considered as a global major cause of cancer death. Surgical resection is the main line of treatment; however, chemo-, radiotherapy and other adjuvant agents are crucial to achieve good outcomes. The tumor microenvironment (TME) is a well-recognized key player in CRC progression, yet the processes linking the cancer cells to its TME are not fully delineated. Autophagy is one of such processes, with a controversial role in the pathogenesis of CRC, with its intricate links to many pathological factors and processes. Autophagy may apparently play conflicting roles in carcinogenesis, but the precise mechanisms determining the overall direction of the process seem to depend on the context. Additionally, it has been established that autophagy has a remarkable effect on the endothelial cells in the TME, the key substrate for angiogenesis that supports tumor metastasis. Favorable response to immunotherapy occurs only in a specific subpopulation of CRC patients, namely the microsatellite instability-high (MSI-H). In view of such limitations of immunotherapy in CRC, modulation of autophagy represents a potential adjuvant strategy to enhance the effect of those relatively safe agents on wider CRC molecular subtypes. In this review, we discussed the molecular control of autophagy in CRC and how autophagy affects different processes and mechanisms that shape the TME. We explored how autophagy contributes to CRC initiation and progression, and how it interacts with tumor immunity, hypoxia, and oxidative stress. The crosstalk between autophagy and the TME in CRC was extensively dissected. Finally, we reported the clinical efforts and challenges in combining autophagy modulators with various cancer-targeted agents to improve CRC patients’ survival and restrain cancer growth.
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Affiliation(s)
- Eglal Mahgoub
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Jalal Taneera
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Nabil Sulaiman
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Medicine, Cairo University, Giza, Egypt
- *Correspondence: Maha Saber-Ayad,
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Xue F, Cheng J, Liu Y, Cheng C, Zhang M, Sui W, Chen W, Hao P, Zhang Y, Zhang C. Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice. Signal Transduct Target Ther 2022; 7:259. [PMID: 35909160 PMCID: PMC9339545 DOI: 10.1038/s41392-022-01054-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 05/06/2022] [Accepted: 06/05/2022] [Indexed: 02/08/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17fl/fl control, A17α-MHCKO control, ADAM17fl/fl diabetic and A17α-MHCKO diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17α-MHCKO and ADAM17fl/fl diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM.
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Affiliation(s)
- Fei Xue
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jing Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yanping Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Cheng Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Meng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wenhai Sui
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Wenqiang Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Panpan Hao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| | - Yun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Cheng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
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Manzoor S, Muhammad JS, Maghazachi AA, Hamid Q. Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance. Front Oncol 2022; 12:924290. [PMID: 35912261 PMCID: PMC9329589 DOI: 10.3389/fonc.2022.924290] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
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Affiliation(s)
- Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Qutayba Hamid,
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Önder GÖ, Sezer G, Özdamar S, Yay A. Melatonin has an inhibitory effect on MCF‐7 and MDA‐MB‐231 human breast cancer cell lines by inducing autophagy and apoptosis. Fundam Clin Pharmacol 2022; 36:1038-1056. [DOI: 10.1111/fcp.12813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/07/2022] [Accepted: 06/30/2022] [Indexed: 12/19/2022]
Affiliation(s)
- Gözde Özge Önder
- Faculty of Medicine, Department of Histology and Embryology Erciyes University Kayseri Turkey
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
| | - Gülay Sezer
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
- Faculty of Medicine, Department of Pharmacology Erciyes University Kayseri Turkey
| | - Saim Özdamar
- Faculty of Medicine, Department of Histology and Embryology Pamukkale University Denizli Turkey
| | - Arzu Yay
- Faculty of Medicine, Department of Histology and Embryology Erciyes University Kayseri Turkey
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
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Pouremamali F, Pouremamali A, Dadashpour M, Soozangar N, Jeddi F. An update of Nrf2 activators and inhibitors in cancer prevention/promotion. Cell Commun Signal 2022; 20:100. [PMID: 35773670 PMCID: PMC9245222 DOI: 10.1186/s12964-022-00906-3] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/09/2022] [Indexed: 01/01/2023] Open
Abstract
NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can increase the sensitivity of the cells to oxidants and electrophiles. Transient Nrf2 activation, by its specific activators, has protective roles against carcinogenesis and cancer development. However, permanent activation of Nrf2 promotes various cancer properties, comprising malignant progression, chemo/radio resistance, and poor patient prognosis. Taken together, these findings suggest that reaching an optimal balance between paradoxical functions of Nrf2 in malignancy may render a selective improvement to identify therapeutic strategies in cancer treatment. In this review, we describe lately discovered Nrf2 inducers and inhibitors, and their chemopreventive and/or anticancer activities. The Nrf2 pathway signifies one of the most significant cell defense procedures against exogenous or endogenous stressors. Certainly, by increasing the expression of several cytoprotective genes, the transcription factor Nrf2 can shelter cells and tissues from multiple sources of damage including electrophilic, xenobiotic, metabolic, and oxidative stress. Notably, the aberrant activation or accumulation of Nrf2, a common event in many tumors, confers a selective advantage to cancer cells and is connected to malignant progression, therapy resistance, and poor prognosis. Therefore, lately, Nrf2 has arisen as a hopeful target in treatment of cancer, and many struggles have been made to detect therapeutic strategies intended at disrupting its pro-oncogenic role. By summarizing the outcomes from past and recent studies, this review provided an overview concerning the Nrf2 pathway and the molecular mechanisms causing Nrf2 hyperactivation in cancer cells. Finally, this paper also described some of the most promising therapeutic approaches that have been successfully employed to counteract Nrf2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.
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