|
1
|
Zhang Y, Gong C, Tao L, Zhai J, Huang F, Zhang S. Involvement of SIRT1-mediated aging in liver diseases. Front Cell Dev Biol 2025; 13:1548015. [PMID: 40052151 PMCID: PMC11882576 DOI: 10.3389/fcell.2025.1548015] [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: 12/19/2024] [Accepted: 01/27/2025] [Indexed: 03/09/2025] Open
Abstract
Liver disease is a significant global health issue, responsible for millions of deaths annually. Aging, characterized by the gradual decline in cellular and physiological functions, impairs tissue regeneration, increases susceptibility to liver diseases, and leads to a decline in liver health. Silent information regulator 1 (SIRT1), a NAD⁺-dependent deacetylase, has emerged as a pivotal factor in modulating age-related changes in the liver. SIRT1 preserves liver function by regulating essential aging-related pathways, including telomere maintenance, epigenetic modifications, cellular senescence, intercellular communication, inflammation, and mitochondrial function. Notably, SIRT1 levels naturally decline with age, contributing to liver disease progression and increased vulnerability to injury. This review summarizes the regulatory role of SIRT1 in aging and its impact on liver diseases such as liver fibrosis, alcoholic associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH), hepatocellular carcinoma (HCC). We also discuss emerging therapeutic approaches, including SIRT1 activators, gene therapy, and nutritional interventions, which are evaluated for their potential to restore SIRT1 function and mitigate liver disease progression. Finally, we highlight future research directions to optimize SIRT1-targeted therapies for clinical applications in age-related liver conditions.
Collapse
Affiliation(s)
- Yueming Zhang
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
| | - Chang Gong
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
| | - Lina Tao
- Department of Pharmacy, The First Hospital of Jilin University, Changchun, China
| | - Jinghui Zhai
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
| | - Fengwei Huang
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
- College of Pharmacy, Jilin University, Changchun, Jilin, China
| | - Sixi Zhang
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
- College of Pharmacy, Jilin University, Changchun, Jilin, China
| |
Collapse
|
|
2
|
Mohan M, Mannan A, Nauriyal A, Singh TG. Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation. Behav Brain Res 2025; 476:115242. [PMID: 39243983 DOI: 10.1016/j.bbr.2024.115242] [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: 08/13/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.
Collapse
Affiliation(s)
- Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Aayush Nauriyal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| |
Collapse
|
|
3
|
Jasim SA, Salahdin OD, Malathi H, Sharma N, Rab SO, Aminov Z, Pramanik A, Mohammed IH, Jawad MA, Gabel BC. Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA). Cell Biochem Biophys 2024; 82:3031-3051. [PMID: 39060914 DOI: 10.1007/s12013-024-01423-5] [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] [Accepted: 07/10/2024] [Indexed: 07/28/2024]
Abstract
Tumor recurrence after curative therapy and hepatocellular carcinoma (HCC) cells' resistance to conventional therapies is the reasons for the worse clinical results of HCC patients. A tiny population of cancer cells with a strong potential for self-renewal, differentiation, and tumorigenesis has been identified as cancer stem cells (CSCs). The discovery of CSC surface markers and the separation of CSC subpopulations from HCC cells have been made possible by recent developments in the study of hepatic (liver) CSCs. Hepatic CSC surface markers include epithelial cell adhesion molecules (EpCAM), CD133, CD90, CD13, CD44, OV-6, ALDH, and K19. CSCs have a significant influence on the development of cancer, invasiveness, self-renewal, metastasis, and drug resistance in HCC, and thus provide a therapeutic chance to treat HCC and avoid its recurrence. Therefore, it is essential to develop treatment approaches that specifically and effectively target hepatic stem cells. Given this, one potential treatment approach is to use particular small interfering RNA (siRNA) to target CSC, disrupting their behavior and microenvironment as well as changing their epigenetic state. The characteristics of CSCs in HCC are outlined in this study, along with new treatment approaches based on siRNA that may be used to target hepatic CSCs and overcome HCC resistance to traditional therapies.
Collapse
Affiliation(s)
| | | | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University, Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh group of Colleges, Jhanjeri, 140307, Mohali, Punjab, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Israa Hussein Mohammed
- College of nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Benien C Gabel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
| |
Collapse
|
|
4
|
Duan X, Xing Z, Qiao L, Qin S, Zhao X, Gong Y, Li X. The role of histone post-translational modifications in cancer and cancer immunity: functions, mechanisms and therapeutic implications. Front Immunol 2024; 15:1495221. [PMID: 39620228 PMCID: PMC11604627 DOI: 10.3389/fimmu.2024.1495221] [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: 09/12/2024] [Accepted: 10/18/2024] [Indexed: 12/11/2024] Open
Abstract
Histones play crucial roles in both promoting and repressing gene expression, primarily regulated through post-translational modifications (PTMs) at specific amino acid residues. Histone PTMs, including methylation, acetylation, ubiquitination, phosphorylation, lactylation, butyrylation, and propionylation, act as important epigenetic markers. These modifications influence not only chromatin compaction but also gene expression. Their importance extends to the treatment and prevention of various human diseases, particularly cancer, due to their involvement in key cellular processes. Abnormal histone modifications and the enzymes responsible for these alterations often serve as critical drivers in tumor cell proliferation, invasion, apoptosis, and stemness. This review introduces key histone PTMs and the enzymes responsible for these modifications, examining their impact on tumorigenesis and cancer progression. Furthermore, it explores therapeutic strategies targeting histone PTMs and offers recommendations for identifying new potential therapeutic targets.
Collapse
Affiliation(s)
- Xiaohong Duan
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Zhiyao Xing
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
| | - Lu Qiao
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Shan Qin
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xuejing Zhao
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Yanhua Gong
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xueren Li
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
| |
Collapse
|
|
5
|
Binarci B, Kilic EK, Dogan T, Cetin Atalay R, Kahraman DC, Nacak Baytas S. Design, synthesis, and evaluation of novel Indole-Based small molecules as sirtuin inhibitors with anticancer activities. Drug Dev Res 2024; 85:e70008. [PMID: 39428864 DOI: 10.1002/ddr.70008] [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: 06/25/2024] [Revised: 10/02/2024] [Accepted: 10/04/2024] [Indexed: 10/22/2024]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, driven mainly by chronic hepatitis infections and metabolic disorders, which highlights the urgent need for novel therapeutic strategies. Sirtuins, particularly SIRT1 are crucial in HCC pathogenesis, making it a promising drug target. Indole-based molecules show potential as therapeutic agents by interacting with key proteins like sirtuins involved in cancer progression. In this study, we designed and synthesized novel indole-based small molecules and investigated their potential sirtuin inhibitory action and anticancer activity on HCC cell lines. Four of the twenty-eight tested small molecules on different cancer types were selected (4 g, 4 h, 4o, and 7j) based on their structure-activity relationship and studied on a panel of HCC cell lines. Compounds had active drug-target interactions with SIRT1 or SIRT2 based on DEEPScreen DTI predictions and docking studies which confirmed that 4o, 4 g, and 7j were most potent in their interaction with SIRT1. Compound 4 g caused the highest sirtuin activity inhibition in vitro and induced G1 arrest and apoptosis in HCC cell lines.
Collapse
Affiliation(s)
- Busra Binarci
- Department of Biological Sciences, METU, Ankara, Turkiye
| | - Ensar Korkut Kilic
- Division of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkiye
| | - Tunca Dogan
- Biological Data Science Lab, Department of Computer Engineering, Hacettepe University, Ankara, Turkiye
- Department of Bioinformatics, Graduate School of Health Sciences, Hacettepe University, Ankara, Turkiye
| | - Rengul Cetin Atalay
- Cancer Systems Biology Laboratory, Department of Health Informatics, Graduate School of Informatics, METU, Ankara, Turkiye
| | - Deniz Cansen Kahraman
- Cancer Systems Biology Laboratory, Department of Health Informatics, Graduate School of Informatics, METU, Ankara, Turkiye
| | - Sultan Nacak Baytas
- Division of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkiye
- Department of Pharmaceutical Chemistry, Graduate School of Health Sciences, Gazi University, Ankara, Turkiye
| |
Collapse
|
|
6
|
Thangavelu L, Altamimi ASA, Ghaboura N, Babu MA, Roopashree R, Sharma P, Pal P, Choudhary C, Prasad GVS, Sinha A, Balaraman AK, Rawat S. Targeting the p53-p21 axis in liver cancer: Linking cellular senescence to tumor suppression and progression. Pathol Res Pract 2024; 263:155652. [PMID: 39437639 DOI: 10.1016/j.prp.2024.155652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/09/2024] [Accepted: 10/11/2024] [Indexed: 10/25/2024]
Abstract
Liver cancer is a major health epidemic worldwide, mainly due to its high mortality rates and limited treatment options. The association of cellular senescence to tumorigenesis and the cancer hallmarks remains a subject of interest in cancer biology. The p53-p21 signalling axis is an important regulator in restoring the cell's balance by supporting tumor suppression and tumorigenesis in liver cancer. We review the novel molecular mechanisms that p53 and its downstream effector, p21, employ to induce cellular senescence, making it last longer, and halt the proliferation of damaged hepatocytes to become tumorous cells. We also examine how dysregulation of this pathway contributes to HCC pathogenesis, proliferation, survival, acquired resistance to apoptosis, and increased invasiveness. Furthermore, we comprehensively describe the molecular cross-talk between the p53-p21 signalling axis and major cell cycle signalling pathways, including Wnt/β-catenin, PI3K/Akt, and TGF-β in liver cancer and provide an overview of promising candidates for chemoprevention and future therapeutic strategies. This review article explores the roles of the p53-p21 pathway in liver cancer, examining its function in promoting cellular senescence under normal conditions and its potential role in cancer progression. It also highlights novel therapeutic drugs and drug targets within the pathway and discusses the implications for treatment strategies and prognosis in liver cancer.
Collapse
Affiliation(s)
- Lakshmi Thangavelu
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Abdulmalik S A Altamimi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Nehmat Ghaboura
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - M Arockia Babu
- Institute of Pharmaceutical Research, GLA UNIVERSITY, Mathura, UP 281406, India.
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Pawan Sharma
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Pusparghya Pal
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - Chhavi Choudhary
- Chandigarh Pharmacy College, Chandigarh Group of College, Jhanjeri, Mohali, Punjab 140307, India
| | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Aashna Sinha
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, India
| | - Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya, Selangor 63000, Malaysia
| | - Sushama Rawat
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, Dehradun 248002, India
| |
Collapse
|
|
7
|
Yu L, Li Y, Song S, Zhang Y, Wang Y, Wang H, Yang Z, Wang Y. The dual role of sirtuins in cancer: biological functions and implications. Front Oncol 2024; 14:1384928. [PMID: 38947884 PMCID: PMC11211395 DOI: 10.3389/fonc.2024.1384928] [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: 02/11/2024] [Accepted: 05/30/2024] [Indexed: 07/02/2024] Open
Abstract
Sirtuins are pivotal in orchestrating numerous cellular pathways, critically influencing cell metabolism, DNA repair, aging processes, and oxidative stress. In recent years, the involvement of sirtuins in tumor biology has garnered substantial attention, with a growing body of evidence underscoring their regulatory roles in various aberrant cellular processes within tumor environments. This article delves into the sirtuin family and its biological functions, shedding light on their dual roles-either as promoters or inhibitors-in various cancers including oral, breast, hepatocellular, lung, and gastric cancers. It further explores potential anti-tumor agents targeting sirtuins, unraveling the complex interplay between sirtuins, miRNAs, and chemotherapeutic drugs. The dual roles of sirtuins in cancer biology reflect the complexity of targeting these enzymes but also highlight the immense therapeutic potential. These advancements hold significant promise for enhancing clinical outcomes, marking a pivotal step forward in the ongoing battle against cancer.
Collapse
Affiliation(s)
- Lu Yu
- Department of Respiratory, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanjiao Li
- Department of Pharmacy, Qionglai Hospital of Traditional Chinese Medicine, Chengdu, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Yalin Zhang
- School of Medicine, University of Electronic Science and Technology of China, Center of Critical Care Medicine, Sichuan Academy of Medical Sciences, Chengdu, China
- Center of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yiping Wang
- Center of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hailian Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science, Nanning, China
| | - Zhengteng Yang
- Department of Medicine, The First Affiliated Hospital of Guangxi University of Traditional Medicine, Nanning, China
| | - Yi Wang
- Center of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science, Nanning, China
| |
Collapse
|
|
8
|
Hashem M, Mohandesi Khosroshahi E, Aliahmady M, Ghanei M, Soofi Rezaie Y, alsadat Jafari Y, rezaei F, Khodaparast eskadehi R, Kia Kojoori K, jamshidian F, Nabavi N, Rashidi M, Hasani Sadi F, Taheriazam A, Entezari M. Non-coding RNA transcripts, incredible modulators of cisplatin chemo-resistance in bladder cancer through operating a broad spectrum of cellular processes and signaling mechanism. Noncoding RNA Res 2024; 9:560-582. [PMID: 38515791 PMCID: PMC10955558 DOI: 10.1016/j.ncrna.2024.01.009] [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: 11/09/2023] [Revised: 01/12/2024] [Accepted: 01/14/2024] [Indexed: 03/23/2024] Open
Abstract
Bladder cancer (BC) is a highly frequent neoplasm in correlation with significant rate of morbidity, mortality, and cost. The onset of BC is predominantly triggered by environmental and/or occupational exposures to carcinogens, such as tobacco. There are two distinct pathways by which BC can be developed, including non-muscle-invasive papillary tumors (NMIBC) and non-papillary (or solid) muscle-invasive tumors (MIBC). The Cancer Genome Atlas project has further recognized key genetic drivers of MIBC along with its subtypes with particular properties and therapeutic responses; nonetheless, NMIBC is the predominant BC presentation among the suffering individuals. Radical cystoprostatectomy, radiotherapy, and chemotherapy have been verified to be the common therapeutic interventions in metastatic tumors, among which chemotherapeutics are more conventionally utilized. Although multiple chemo drugs have been broadly administered for BC treatment, cisplatin is reportedly the most effective chemo drug against the corresponding malignancy. Notwithstanding, tumor recurrence is usually occurred following the consumption of cisplatin regimens, particularly due to the progression of chemo-resistant trait. In this framework, non-coding RNAs (ncRNAs), as abundant RNA transcripts arise from the human genome, are introduced to serve as crucial contributors to tumor expansion and cisplatin chemo-resistance in bladder neoplasm. In the current review, we first investigated the best-known ncRNAs, i.e. microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), correlated with cisplatin chemo-resistance in BC cells and tissues. We noticed that these ncRNAs could mediate the BC-related cisplatin-resistant phenotype through diverse cellular processes and signaling mechanisms, reviewed here. Eventually, diagnostic and prognostic potential of ncRNAs, as well as their therapeutic capabilities were highlighted in regard to BC management.
Collapse
Affiliation(s)
- Mehrdad Hashem
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Melika Aliahmady
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Morvarid Ghanei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Yasamin Soofi Rezaie
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Yasamin alsadat Jafari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Fatemeh rezaei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Ramtin Khodaparast eskadehi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Kimia Kia Kojoori
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - faranak jamshidian
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Mohsen Rashidi
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Farzaneh Hasani Sadi
- General Practitioner, Kerman University of Medical Sciences, Kerman, 7616913555, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| |
Collapse
|
|
9
|
Chan HY, Ramasamy TS, Chung FFL, Teow SY. Role of sirtuin 1 (SIRT1) in regulation of autophagy and nuclear factor-kappa Beta (NF-ĸβ) pathways in sorafenib-resistant hepatocellular carcinoma (HCC). Cell Biochem Biophys 2024; 82:959-968. [PMID: 38466472 DOI: 10.1007/s12013-024-01247-3] [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] [Accepted: 02/29/2024] [Indexed: 03/13/2024]
Abstract
Hepatocellular carcinoma (HCC) remains a major global health problem with high incidence and mortality. Diagnosis of HCC at late stages and tumour heterogeneity in patients with different genetic profiles are known factors that complicate the disease treatment. HCC therapy becomes even more challenging in patients with drug resistance such as resistance to sorafenib, which is a common drug used in HCC patients. Sorafenib resistance can further aggravate HCC by regulating various oncogenic pathways such as autophagy and nuclear factor-kappa Beta (NF-ĸβ) signalling. Sirtuin 1 (SIRT1), is a nicotinamide adenosine dinucleotide (NAD)-dependent histone deacetylases that regulates various metabolic and oncogenic events such as cell survival, apoptosis, autophagy, tumourigenesis, metastasis and drug resistance in various cancers, but its role in HCC, particularly in sorafenib resistance is underexplored. In this study, we generated sorafenib-resistant HepG2 and Huh-7 liver cancer cell models to investigate the role of SIRT1 and its effect on autophagy and nuclear factor-kappa Beta (NF-ĸβ) signalling pathways. Western blot analysis showed increased SIRT1, altered autophagy pathway and activated NF-ĸβ signalling in sorafenib-resistant cells. SIRT1-silenced HCC cells demonstrated down-regulated autophagy in both parental and chemoresistant cells. This may occur through the deacetylation of key autophagy molecules such as FOXO3, beclin 1, ATGs and LC3 by SIRT1, highlighting the role of SIRT1 in autophagy induction. Silencing of SIRT1 also resulted in activated NF-ĸβ signalling. This is because SIRT1 failed to deacetylate p65 subunit of NF-κB, translocate the NF-κB from nucleus to cytoplasm, and suppress NF-κB activity due to the silencing. Hence, the NF-κB transcriptional activity was restored. These findings summarize the role of SIRT1 in autophagy/NF-ĸβ regulatory axis, with a similar trend observed in both parental and sorafenib-resistant cells. The present work promotes a better understanding of the role of SIRT1 in autophagy and NF-ĸβ signalling in HCC and sorafenib-resistant HCC. As some key proteins in these pathways are potential therapeutic targets, a better understanding of SIRT1/autophagy/NF-ĸβ axis could further improve the therapeutic strategies against HCC.
Collapse
Affiliation(s)
- Hui-Yin Chan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, 47500 Subang Jaya, Bandar, Sunway, Selangor Darul Ehsan, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Felicia Fei-Lei Chung
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, 47500 Subang Jaya, Bandar, Sunway, Selangor Darul Ehsan, Malaysia
| | - Sin-Yeang Teow
- Department of Biology, College of Science, Mathematics and Technology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou, 325060, Zhejiang Provinve, China.
- Wenzhou Municipal Key Lab for Applied Biomedical and Biopharmaceutical Informatics, Ouhai, Wenzhou, 325060, Zhejiang Province, China.
- Zhejiang Bioinformatics International Science and Technology Cooperation Center, Ouhai, Wenzhou, 325060, Zhejiang Province, China.
- Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morries Ave, Union, NJ, 07083, USA.
| |
Collapse
|
|
10
|
Hasona NA, Elsabahy M, Shaker OG, Zaki O, Ayeldeen G. The Implication of Growth Arrest-Specific 5 rs145204276 Polymorphism and Serum Expression of Sirtuin 1, Transforming Growth Factor-Beta, and microRNA-182 in Breast Cancer. Clin Med Insights Oncol 2024; 18:11795549241227415. [PMID: 38322669 PMCID: PMC10846042 DOI: 10.1177/11795549241227415] [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: 06/24/2023] [Accepted: 01/01/2024] [Indexed: 02/08/2024] Open
Abstract
Background Breast cancer (BC) patients have a higher chance of survival if it is diagnosed at an early stage, which is essential for efficient treatment of the condition. The results of an elevated risk of cancer, including BC, previously associated with the ins/del polymorphism rs145204276 in the promoter region of growth arrest-specific 5 (GAS5) are still up for debate. Thus, this study aimed to appraise the frequency of the GAS5 rs145204276 variant with BC risk and demonstrate the potential impact of the sirtuin 1 (SIRT-1), transforming growth factor-beta (TGF-β), and microRNA-182 (miR-182) expression and their diagnostic value in BC. Methods Blood samples of 155 patients with BC and fibroadenoma and 80 healthy controls were analyzed for GAS5 rs145204276 single nucleotide polymorphism (SNP), SIRT-1, TGF-β, and miRNA-182 expression levels. Results Ins/ins genotype and ins allele frequencies for GAS5 rs145204276 were considerably higher in BC patients compared with controls. Patients with BC had significantly greater serum levels of TGF-β, miR-182, and SIRT-1 expression. Conclusions The SIRT-1, TGF-β, and miR-182 genes provide novel, noninvasive diagnostic biomarkers for BC.
Collapse
Affiliation(s)
- Nabil A Hasona
- Department of Biochemistry, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
| | - Mahmoud Elsabahy
- Badr University in Cairo Research Center, Badr University in Cairo, Badr City, Egypt
| | - Olfat G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Othman Zaki
- Department of Clinical Pathology, Faculty of Medicine, Damietta University, New Damietta, Egypt
| | - Ghada Ayeldeen
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| |
Collapse
|
|
11
|
Li B, Bo S, Sheng Z, Zhu H, Jiang Y, Yang B. Hepatoprotective Activity and Mechanisms of Prenylated Stilbenoids. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:1618-1629. [PMID: 38189644 DOI: 10.1021/acs.jafc.3c09515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Dietary prenylated stilbenoids, found in various food sources, offer multiple health benefits, including liver protection. However, the underlying mechanisms of hepatoprotection remain unclear. In this study, we synthesized 13 natural prenylated stilbenoids and examined their hepatoprotective activities, with silent mating type information regulation 2 homologue-1 (SIRT1) as the primary target for screening. Among all of the prenylated stilbenoids tested, 4-C-geranyl oxyresveratrol demonstrated superior performance. It activated SIRT1 activity more effectively than resveratrol, a well-known SIRT1 activator. To further investigate the mechanism of liver protection, two in vitro models were used: the palmitic acid-induced lipid accumulation model and the H2O2-induced apoptosis model. Our findings suggested that 4-C-geranyl oxyresveratrol mitigated lipid accumulation through the SIRT1-PGC1α pathway, reduced apoptosis via the SIRT1-p53-p21 pathway, and exerted antioxidant effects through the SIRT1-Nrf2 pathway. These findings provide new insights into the chemical basis of the health benefits of prenylated stilbenoids and their potential use as functional food additives.
Collapse
Affiliation(s)
- Bailin Li
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shengtao Bo
- Zhaoqing Public Security Judicial Appraisal Center, Zhaoqing 526000, China
| | - Zhili Sheng
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hong Zhu
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yueming Jiang
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bao Yang
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| |
Collapse
|
|
12
|
Isachesku E, Braicu C, Pirlog R, Kocijancic A, Busuioc C, Pruteanu LL, Pandey DP, Berindan-Neagoe I. The Role of Non-Coding RNAs in Epigenetic Dysregulation in Glioblastoma Development. Int J Mol Sci 2023; 24:16320. [PMID: 38003512 PMCID: PMC10671451 DOI: 10.3390/ijms242216320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/04/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
Glioblastoma (GBM) is a primary brain tumor arising from glial cells. The tumor is highly aggressive, the reason for which it has become the deadliest brain tumor type with the poorest prognosis. Like other cancers, it compromises molecular alteration on genetic and epigenetic levels. Epigenetics refers to changes in gene expression or cellular phenotype without the occurrence of any genetic mutations or DNA sequence alterations in the driver tumor-related genes. These epigenetic changes are reversible, making them convenient targets in cancer therapy. Therefore, we aim to review critical epigenetic dysregulation processes in glioblastoma. We will highlight the significant affected tumor-related pathways and their outcomes, such as regulation of cell cycle progression, cell growth, apoptosis, angiogenesis, cell invasiveness, immune evasion, or acquirement of drug resistance. Examples of molecular changes induced by epigenetic modifications, such as DNA epigenetic alterations, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) regulation, are highlighted. As understanding the role of epigenetic regulators and underlying molecular mechanisms in the overall pro-tumorigenic landscape of glioblastoma is essential, this literature study will provide valuable insights for establishing the prognostic or diagnostic value of various non-coding transcripts, including miRNAs.
Collapse
Affiliation(s)
- Ekaterina Isachesku
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania (C.B.); (R.P.); (L.-L.P.)
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania (C.B.); (R.P.); (L.-L.P.)
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania (C.B.); (R.P.); (L.-L.P.)
| | - Anja Kocijancic
- Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway; (A.K.)
| | - Constantin Busuioc
- Department of Pathology, National Institute of Infectious Disease, 021105 Bucharest, Romania;
- Department of Pathology, Onco Team Diagnostic, 010719 Bucharest, Romania
| | - Lavinia-Lorena Pruteanu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania (C.B.); (R.P.); (L.-L.P.)
- Department of Chemistry and Biology, North University Center, Technical University of Cluj-Napoca, 430122 Baia Mare, Romania
| | - Deo Prakash Pandey
- Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway; (A.K.)
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania (C.B.); (R.P.); (L.-L.P.)
| |
Collapse
|
|
13
|
Jiang Y, Miao X, Wu Z, Xie W, Wang L, Liu H, Gong W. Targeting SIRT1 synergistically improves the antitumor effect of JQ-1 in hepatocellular carcinoma. Heliyon 2023; 9:e22093. [PMID: 38045194 PMCID: PMC10692793 DOI: 10.1016/j.heliyon.2023.e22093] [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: 06/25/2023] [Revised: 10/31/2023] [Accepted: 11/03/2023] [Indexed: 12/05/2023] Open
Abstract
Bromodomain and extraterminal domain protein inhibitors have shown therapeutic promise in hepatocellular carcinoma. However, resistance to bromodomain and extraterminal domain protein inhibitors has emerged in preclinical trials, presenting an immense clinical challenge, and the mechanisms are unclear. In this study, we found that overexpression of SIRT1 induced by JQ-1, a bromodomain and extraterminal domain protein inhibitor, may confer resistance to JQ-1 in hepatocellular carcinoma. SIRT1 protein expression was higher in hepatocellular carcinoma tissues than in normal tissues, and this phenotype was correlated with a poor prognosis. Cotreatment with JQ-1 and the SIRT1 inhibitor EX527 synergistically suppressed proliferation and blocked cell cycle progression in hepatocellular carcinoma cells. Combined administration of JQ-1 and EX527 successfully reduced the tumor burden in vivo. In addition, JQ-1 mediated AMPK/p-AMPK axis activation to upregulate SIRT1 protein expression and enhanced autophagy to inhibit cell apoptosis. Activation of AMPK could alleviate the antitumor effect of the combination of JQ-1 and EX527 on hepatocellular carcinoma cells. Furthermore, inhibition of SIRT1 further enhanced the antitumor effect of JQ-1 by blocking protective autophagy in hepatocellular carcinoma. Our study proposes a novel and efficacious therapeutic strategy of a BET inhibitor combined with a SIRT1 inhibitor for hepatocellular carcinoma.
Collapse
Affiliation(s)
- Yuancong Jiang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Department of Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Xiaolong Miao
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- The Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zelai Wu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Weixun Xie
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Wang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Han Liu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Weihua Gong
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
14
|
Paula Ceballos M, Darío Quiroga A, Palma NF. Role of sirtuins in hepatocellular carcinoma progression and multidrug resistance: Mechanistical and pharmacological perspectives. Biochem Pharmacol 2023; 212:115573. [PMID: 37127248 DOI: 10.1016/j.bcp.2023.115573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide. Therapeutic strategies are still challenging due to the high relapse rate after surgery and multidrug resistance (MDR). It is essential to better understand the mechanisms for HCC progression and MDR for the development of new therapeutic strategies. Mammalian sirtuins (SIRTs), a family of seven members, are related to tumor progression, MDR and prognosis and were proposed as potential prognostic markers, as well as therapeutic targets for treating cancer. SIRT1 is the most studied member and is overexpressed in HCC, playing an oncogenic role and predicting poor prognosis. Several manuscripts describe the role of SIRTs2-7 in HCC; most of them report an oncogenic role for SIRT2 and -7 and a suppressive role for SIRT3 and -4. The scenario is more confusing for SIRT5 and -6, since information is contradictory and scarce. For SIRT1 many inhibitors are available and they seem to hold therapeutic promise in HCC. For the other members the development of specific modulators has just started. This review is aimed to describe the features of SIRTs1-7 in HCC, and the role they play in the onset and progression of the disease. Also, when possible, we will depict the information related to the SIRTs modulators that have been tested in HCC and their possible implication in MDR. With this, we hope to clarify the role of each member in HCC and to shed some light on the most successful strategies to overcome MDR.
Collapse
Affiliation(s)
- María Paula Ceballos
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina.
| | - Ariel Darío Quiroga
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina; Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipachs 570 (S2002LRL), Rosario, Argentina; Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS) Sede Regional Rosario, Universidad Abierta Interamericana, Av. Pellegrini 1618 (S2000BUG), Rosario, Argentina
| | - Nicolás Francisco Palma
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina; Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipachs 570 (S2002LRL), Rosario, Argentina
| |
Collapse
|
|
15
|
Nakano T, Chen CL, Chen IH, Tseng HP, Chiang KC, Lai CY, Hsu LW, Goto S, Lin CC, Cheng YF. Overexpression of miR-4669 Enhances Tumor Aggressiveness and Generates an Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma: Its Clinical Value as a Predictive Biomarker. Int J Mol Sci 2023; 24:ijms24097908. [PMID: 37175615 PMCID: PMC10177802 DOI: 10.3390/ijms24097908] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Accumulating evidence suggests the involvement of tumor-derived exosomes in the development and recurrence of hepatocellular carcinoma (HCC). We previously identified miR-4669 as a highly expressed microRNA in circulating exosomes obtained from patients with post-transplant HCC recurrence. This study aimed to explore how overexpression of miR-4669 affects HCC development and recurrence. The impact of miR-4669 overexpression in Hep3B cells on tumor cell behavior and the tumor microenvironment was evaluated in vitro. In addition, the clinical value of exosomal miR-4669 for the prediction of treatment response to HCC downstaging therapies and following post-transplant HCC recurrence was explored. Overexpression of miR-4669 enhanced migration ability and led to acquired sorafenib resistance with an elevation of sirtuin 1 and long noncoding RNA associated with microvascular invasion. Active release of tumor-derived exosomes and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) contributed to generating an immunosuppressive tumor microenvironment through the induction of M2 macrophage polarization. The retrospective analysis demonstrated the clinical value of exosomal miR-4669 for predicting treatment response to HCC downstaging therapies and for risk assessment of post-transplant HCC recurrence. In summary, the present data demonstrate the impact of exosomal miR-4669 on HCC recurrence through the enhancement of tumor aggressiveness and generation of an immunosuppressive tumor microenvironment.
Collapse
Affiliation(s)
- Toshiaki Nakano
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - I-Hsuan Chen
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Hui-Peng Tseng
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Kuei-Chen Chiang
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Chia-Yun Lai
- Liver Transplantation Center, Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Li-Wen Hsu
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Shigeru Goto
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Nobeoka Medical Check Center, Fukuoka Institution of Occupational Health, Nobeoka 882-0872, Japan
| | - Chih-Che Lin
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Yu-Fan Cheng
- Liver Transplantation Center, Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| |
Collapse
|
|
16
|
Singh AK, Singh SV, Kumar R, Kumar S, Senapati S, Pandey AK. Current therapeutic modalities and chemopreventive role of natural products in liver cancer: Progress and promise. World J Hepatol 2023; 15:1-18. [PMID: 36744169 PMCID: PMC9896505 DOI: 10.4254/wjh.v15.i1.1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/02/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year, with an estimated 5-year survival rate of 30%–35% after diagnosis. Hepatocellular carcinoma (HCC) constitutes a significant subtype of liver cancer (approximate75%) and is considered primary liver cancer. Treatment for liver cancer mainly depends on the stage of its progression, where surgery including, hepatectomy and liver transplantation, and ablation and radiotherapy are the prime choice. For advanced liver cancer, various drugs and immunotherapy are used as first-line treatment, whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins. Sorafenib and lenvatinib are first-line therapies, while regorafenib and ramucirumab are second-line therapy. Various metabolic and signaling pathways such as Notch, JAK/ STAT, Hippo, TGF-β, and Wnt have played a critical role during HCC progression. Dysbiosis has also been implicated in liver cancer. Drug-induced toxicity is a key obstacle in the treatment of liver cancer, necessitating the development of effective and safe medications, with natural compounds such as resveratrol, curcumin, diallyl sulfide, and others emerging as promising anticancer agents. This review highlights the current status of liver cancer research, signaling pathways, therapeutic targets, current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.
Collapse
Affiliation(s)
- Amit Kumar Singh
- Department of Botany, Government Naveen Girls College, Balod (Hemchand Yadav University), Durg, Chattisgarh, India
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
| | - Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
- Department of Biochemistry, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Shashank Kumar
- Department of Biochemistry, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Sabyasachi Senapati
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
| |
Collapse
|
|
17
|
Is Fasting Good When One Is at Risk of Liver Cancer? Cancers (Basel) 2022; 14:cancers14205084. [PMID: 36291868 PMCID: PMC9600146 DOI: 10.3390/cancers14205084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide, is a multistep process that usually develops in the background of cirrhosis, but also in a non-cirrhotic state in patients with non-alcoholic fatty liver disease (NAFLD) or viral hepatis. Emerging evidence suggests that intermittent fasting can reduce the risk of cancer development and could improve response and tolerance to treatment through the metabolic and hormonal adaptations induced by the low energy availability that finally impairs cancer cells’ adaptability, survival and growth. The current review will outline the beneficial effects of fasting in NAFLD/NASH patients and the possible mechanisms that can prevent HCC development, including circadian clock re-synchronization, with a special focus on the possibility of applying this dietary intervention to cirrhotic patients.
Collapse
|
|
18
|
All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma. Biomedicines 2022; 10:biomedicines10102351. [PMID: 36289617 PMCID: PMC9598942 DOI: 10.3390/biomedicines10102351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/16/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022] Open
Abstract
Cathepsins are lysosomal proteases that are essential to maintain cellular physiological homeostasis and are involved in multiple processes, such as immune and energy regulation. Predominantly, cathepsins reside in the lysosomal compartment; however, they can also be secreted by cells and enter the extracellular space. Extracellular cathepsins have been linked to several pathologies, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). NASH is an increasingly important risk factor for the development of HCC, which is the third leading cause of cancer-related deaths and poses a great medical and economic burden. While information regarding the involvement of cathepsins in NASH-induced HCC (NASH-HCC) is limited, data to support the role of cathepsins in either NASH or HCC is accumulating. Since cathepsins play a role in both NASH and HCC, it is likely that the role of cathepsins is more significant in NASH-HCC compared to HCC derived from other etiologies. In the current review, we provide an overview on the available data regarding cathepsins in NASH and HCC, argue that cathepsins play a key role in the transition from NASH to HCC, and shed light on therapeutic options in this context.
Collapse
|
|
19
|
YAP and TAZ: Monocorial and bicorial transcriptional co-activators in human cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188756. [PMID: 35777600 DOI: 10.1016/j.bbcan.2022.188756] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/09/2022] [Accepted: 06/23/2022] [Indexed: 12/17/2022]
Abstract
The transcriptional regulators YAP and TAZ are involved in numerous physiological processes including organ development, growth, immunity and tissue regeneration. YAP and TAZ dysregulation also contribute to tumorigenesis, thereby making them attractive cancer therapeutic targets. Arbitrarily, YAP and TAZ are often considered as a single protein, and are referred to as YAP/TAZ in most studies. However, increasing experimental evidences documented that YAP and TAZ perform both overlapping and distinct functions in several physiological and pathological processes. In addition to regulating distinct processes, YAP and TAZ are also regulated by distinct upstream cues. The aim of the review is to describe the distinct roles of YAP and TAZ focusing particularly on cancer. Therapeutic strategies targeting either YAP and TAZ proteins or only one of them should be carefully evaluated. Selective targeting of YAP or TAZ may in fact impair different pathways and determine diverse clinical outputs.
Collapse
|
|
20
|
Järvenpää J, Rahnasto-Rilla M, Lahtela-Kakkonen M, Küblbeck J. Profiling the regulatory interplay of BET bromodomains and Sirtuins in cancer cell lines. Biomed Pharmacother 2022; 147:112652. [DOI: 10.1016/j.biopha.2022.112652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/14/2022] [Accepted: 01/14/2022] [Indexed: 12/27/2022] Open
|
|
21
|
Purushotham N, Singh M, Paramesha B, Kumar V, Wakode S, Banerjee SK, Poojary B, Asthana S. Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors. RSC Adv 2022; 12:3809-3827. [PMID: 35425455 PMCID: PMC8981170 DOI: 10.1039/d1ra06149f] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 01/10/2022] [Indexed: 12/27/2022] Open
Abstract
Owing to its presence in several biological processes, Sirt1 acts as a potential therapeutic target for many diseases. Here, we report the structure-based designing and synthesis of two distinct series of novel Sirt1 inhibitors, benzimidazole mono-peptides and amino-acid derived 5-pyrazolyl methylidene rhodanine carboxylic acid. The compounds were evaluated for in vitro enzyme-based and cell-based Sirt1 inhibition assay, and cytotoxic-activity in both liver and breast cancer cells. The tryptophan conjugates i.e.13h (IC50 = 0.66 μM, ΔG bind = -1.1 kcal mol-1) and 7d (IC50 = 0.77 μM, ΔG bind = -4.4 kcal mol-1) demonstrated the maximum efficacy to inhibit Sirt1. The MD simulation unveiled that electrostatic complementarity at the substrate-binding-site through a novel motif "SLxVxP(V/F)A" could be a cause of increased Sirt1 inhibition by 13h and 13l over Sirt2 in cell-based assay, as compared to the control Ex527 and 7d. Finally, this study highlights novel molecules 7d and 13h, along with a new key hot-spot in Sirt1, which could be used as a starting lead to design more potent and selective sirtuin inhibitors as a potential anticancer molecule.
Collapse
Affiliation(s)
- Nikil Purushotham
- Department of Studies in Chemistry, Mangalore University Mangalagangotri Karnataka-574 199 India +91 9686940403
| | - Mrityunjay Singh
- Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster Faridabad Haryana-121001 India +91 1292876475 +91 1292876489 +91 8447568689
- Delhi Institute of Pharmaceutical Sciences and Research, DPSR University M.B Road, Pushp Vihar, Sector 3 New Delhi 110017 India
| | - Bugga Paramesha
- Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster Faridabad Haryana-121001 India +91 1292876475 +91 1292876489 +91 8447568689
| | - Vasantha Kumar
- Department of Studies in Chemistry, Mangalore University Mangalagangotri Karnataka-574 199 India +91 9686940403
| | - Sharad Wakode
- Delhi Institute of Pharmaceutical Sciences and Research, DPSR University M.B Road, Pushp Vihar, Sector 3 New Delhi 110017 India
| | - Sanjay K Banerjee
- Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster Faridabad Haryana-121001 India +91 1292876475 +91 1292876489 +91 8447568689
| | - Boja Poojary
- Department of Studies in Chemistry, Mangalore University Mangalagangotri Karnataka-574 199 India +91 9686940403
| | - Shailendra Asthana
- Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster Faridabad Haryana-121001 India +91 1292876475 +91 1292876489 +91 8447568689
| |
Collapse
|
|
22
|
MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1. Cell Death Dis 2022; 13:35. [PMID: 35013144 PMCID: PMC8748751 DOI: 10.1038/s41419-021-04491-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/02/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022]
Abstract
As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.
Collapse
|
|
23
|
Wang J, Wei B, Thakur K, Wang CY, Li KX, Wei ZJ. Transcriptome Analysis Reveals the Anti-cancerous Mechanism of Licochalcone A on Human Hepatoma Cell HepG2. Front Nutr 2022; 8:807574. [PMID: 34988109 PMCID: PMC8720858 DOI: 10.3389/fnut.2021.807574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma is a malignancy with a low survival rate globally, and there is imperative to unearth novel natural phytochemicals as effective therapeutic strategies. Licochalcone A is a chalcone from Glycyrrhiza that displayed various pharmacological efficacy. A globally transcriptome analysis was carried out to reveal the gene expression profiling to explore Licochalcone A's function as an anti-cancer phytochemical on HepG2 cells and investigate its potential mechanisms. Altogether, 6,061 dysregulated genes were detected (3,414 up-regulated and 2,647 down-regulated). SP1 was expected as the transcription factor that regulates the functions of most screened genes. GO and KEGG analysis was conducted, and the MAPK signaling pathway and the FoxO signaling pathway were two critical signal pathways. Protein-protein interaction (PPI) network analysis based on STRING platform to discover the hub genes (MAPK1, ATF4, BDNF, CASP3, etc.) in the MAPK signaling pathway and (AKT3, GADD45A, IL6, CDK2, CDKN1A, etc.) the FoxO signaling pathway. The protein level of essential genes that participated in significant pathways was consistent with the transcriptome data. This study will provide an inclusive understanding of the potential anti-cancer mechanism of Licochalcone A on hepatocellular, signifying Licochalcone A as a promising candidate for cancer therapy.
Collapse
Affiliation(s)
- Jun Wang
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Bo Wei
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Kiran Thakur
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.,School of Biological Science and Engineering, North Minzu University, Yinchuan, China
| | - Chu-Yan Wang
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Ke-Xin Li
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Zhao-Jun Wei
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.,School of Biological Science and Engineering, North Minzu University, Yinchuan, China
| |
Collapse
|
|
24
|
Watroba M, Szukiewicz D. Sirtuins at the Service of Healthy Longevity. Front Physiol 2021; 12:724506. [PMID: 34899370 PMCID: PMC8656451 DOI: 10.3389/fphys.2021.724506] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Sirtuins may counteract at least six hallmarks of organismal aging: neurodegeneration, chronic but ineffective inflammatory response, metabolic syndrome, DNA damage, genome instability, and cancer incidence. Moreover, caloric restriction is believed to slow down aging by boosting the activity of some sirtuins through activating adenosine monophosphate-activated protein kinase (AMPK), thus raising the level of intracellular nicotinamide adenine dinucleotide (NAD+) by stimulating NAD+ biosynthesis. Sirtuins and their downstream effectors induce intracellular signaling pathways related to a moderate caloric restriction within cells, mitigating reactive oxygen species (ROS) production, cell senescence phenotype (CSP) induction, and apoptosis as forms of the cellular stress response. Instead, it can promote DNA damage repair and survival of cells with normal, completely functional phenotypes. In this review, we discuss mechanisms of sirtuins action toward cell-conserving phenotype associated with intracellular signaling pathways related to moderate caloric restriction, as well as some tissue-specific functions of sirtuins, especially in the central nervous system, heart muscle, skeletal muscles, liver, kidneys, white adipose tissue, hematopoietic system, and immune system. In this context, we discuss the possibility of new therapeutic approaches.
Collapse
Affiliation(s)
- Mateusz Watroba
- Department of Biophysics, Physiology and Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland
| | - Dariusz Szukiewicz
- Department of Biophysics, Physiology and Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland
| |
Collapse
|
|
25
|
Pant K, Peixoto E, Richard S, Biswas A, O'Sullivan MG, Giama N, Ha Y, Yin J, Carotenuto P, Salati M, Ren Y, Yang R, Franco B, Roberts LR, Gradilone SA. Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma. Hepatology 2021; 74:3235-3248. [PMID: 34322899 DOI: 10.1002/hep.32080] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Sirtuin 1 (SIRT1) is a complex NAD+ -dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1-induced destabilization of primary cilia in cholangiocarcinoma (CCA). APPROACH AND RESULTS A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)-mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD -producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1-overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α-tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma-associated oncogene 1, phosphorylated extracellular signal-regulated kinase, and IL-6) expression. CONCLUSIONS In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.
Collapse
Affiliation(s)
- Kishor Pant
- The Hormel Institute, University of Minnesota, Austin, MN
| | | | - Seth Richard
- The Hormel Institute, University of Minnesota, Austin, MN
| | | | - M Gerard O'Sullivan
- Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, St. Paul, MN
| | - Nasra Giama
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Yeonjung Ha
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Jun Yin
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
| | - Pietro Carotenuto
- TIGEM, Telethon Institute of Genetics and Medicine, and Medical Genetics, Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Massimiliano Salati
- Medical Oncology Unit, Modena Cancer Centre, PhD Program Clinical and Experimental Medicine, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Yanan Ren
- The Hormel Institute, University of Minnesota, Austin, MN
| | - Rendong Yang
- The Hormel Institute, University of Minnesota, Austin, MN
| | - Brunella Franco
- TIGEM, Telethon Institute of Genetics and Medicine, and Medical Genetics, Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Lewis R Roberts
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Sergio A Gradilone
- The Hormel Institute, University of Minnesota, Austin, MN.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| |
Collapse
|
|
26
|
Carbone A, De Santis E, Cela O, Giambra V, Miele L, Marrone G, Grieco A, Buschbeck M, Capitanio N, Mazza T, Mazzoccoli G. The Histone Variant MacroH2A1 Impacts Circadian Gene Expression and Cell Phenotype in an In Vitro Model of Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9081057. [PMID: 34440260 PMCID: PMC8391426 DOI: 10.3390/biomedicines9081057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. A foremost risk factor for HCC is obesity/metabolic syndrome-related non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which is prompted by remarkable changes in transcription patterns of genes enriching metabolic, immune/inflammatory, and circadian pathways. Epigenetic mechanisms play a role in NAFLD-associated HCC, and macroH2A1, a variant of histone H2A, is involved in the pathogenesis modulating the expression of oncogenes and/or tumor suppressor genes and interacting with SIRT1, which crucially impacts the circadian clock circuitry. Hence, we aimed to appraise if and how macroH2A1 regulated the expression patterns of circadian genes in the setting of NAFLD-associated HCC. We took advantage of an in vitro model of liver cancer represented by HepG2 (human hepatocarcinoma) cells stably knocked down for macroH2A1 and conducted whole transcriptome profiling and deep phenotyping analysis. We found up-regulation of PER1 along with several deregulated circadian genes, enriching several important pathways and functions related to cancer onset and progression, such as epithelial-to-mesenchymal transition, cell cycle deregulation, and DNA damage. PER1 silencing partially mitigated the malignant phenotype induced by the loss of macroH2A1 in HCC cells. In conclusion, our findings suggest a modulatory role for the core circadian protein PER1 in liver carcinogenesis in the context of a lack of the macroH2A1 epigenetic and transcriptional landscape.
Collapse
Affiliation(s)
- Annalucia Carbone
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Elisabetta De Santis
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (E.D.S.); (V.G.)
| | - Olga Cela
- Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy; (O.C.); (N.C.)
| | - Vincenzo Giambra
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (E.D.S.); (V.G.)
| | - Luca Miele
- Fondazione Policlinico Universitario A. Gemelli-IRCCS, Catholic University of the Sacred Heart, 00168 Rome, Italy; (L.M.); (G.M.); (A.G.)
| | - Giuseppe Marrone
- Fondazione Policlinico Universitario A. Gemelli-IRCCS, Catholic University of the Sacred Heart, 00168 Rome, Italy; (L.M.); (G.M.); (A.G.)
| | - Antonio Grieco
- Fondazione Policlinico Universitario A. Gemelli-IRCCS, Catholic University of the Sacred Heart, 00168 Rome, Italy; (L.M.); (G.M.); (A.G.)
| | - Marcus Buschbeck
- Josep Carreras Leukaemia Research Institute, IJC Building, Can Ruti Campus Ctra de Can Ruti, Camí de les Escoles s/n, 08916 Badalona, Spain;
| | - Nazzareno Capitanio
- Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy; (O.C.); (N.C.)
| | - Tommaso Mazza
- Bioinformatics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
- Correspondence: ; Tel./Fax: +39-(0882)-410-255
| |
Collapse
|
|
27
|
Zia A, Sahebdel F, Farkhondeh T, Ashrafizadeh M, Zarrabi A, Hushmandi K, Samarghandian S. A review study on the modulation of SIRT1 expression by miRNAs in aging and age-associated diseases. Int J Biol Macromol 2021; 188:52-61. [PMID: 34364937 DOI: 10.1016/j.ijbiomac.2021.08.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/15/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023]
Abstract
Sirtuin-1 (SIRT1) as a NAD + -dependent Class III protein deacetylase, involves in longevity and various cellular physiological processes. SIRT1 via deacetylating transcription factors regulates cell growth, inflammation, metabolism, hypoxic responses, cell survival, senescence, and aging. MicroRNAs (miRNAs) are short non-coding RNAs that modulate the expression of target genes in a post-transcriptional manner. Recent investigations have exhibited that miRNAs have an important role in regulating cell growth, development, stress responses, tumor formation and suppression, cell death, and aging. In the present review, we summarize recent findings about the roles of miRNAs in regulating SIRT1 and SIRT1-associated signaling cascade and downstream effects, like apoptosis and aging. Here we introduce and discuss how activity and expression of SIRT1 are modulated by miRNAs and further review the therapeutic potential of targeting miRNAs for age-associated diseases that involve SIRT1 dysfunction. Although at its infancy, research on the roles of miRNAs in aging and their function through modulating SIRT1 may provide new insights in deciphering the key molecular pathways related to aging and age-associated disorders.
Collapse
Affiliation(s)
- Aliabbas Zia
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Faezeh Sahebdel
- Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran; Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey
| | - Ali Zarrabi
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey
| | - Kiavash Hushmandi
- Faculty of Veterinary Medicine, Department of Food Hygiene and Quality Control, Division of epidemiology, University of Tehran, Tehran, Iran
| | - Saeed Samarghandian
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
| |
Collapse
|
|
28
|
Xiang H, Luo M, Hou P, Xiao Z, Huang Z, Feng Q, Zhang R, Li Y, Wu L. miR-124-3p combined with miR-506-3p delay hepatic carcinogenesis via modulating sirtuin 1. Biomarkers 2021; 26:196-206. [PMID: 33401967 DOI: 10.1080/1354750x.2020.1854856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/15/2020] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Our study aimed at exploring whether miR-124-3p and miR-506-3p collaboratively modulated sirtuin 1 (SIRT1) protein expression in liver cancer. Materials and methods: In this study, cell viability, migration and invasion were assessed using CCK8 and transwell assays, respectively. Immunohistochemical (IHC) staining and immunoblotting analysis were performed to evaluate SIRT1 protein expression levels in tissue specimens and cell lines. Moreover, the nude-mouse transplanted tumour model was used to assess liver cancer cell growth in vivo. Results: Our results showed that SIRT1 protein levels were significantly up-regulated in liver cancer tissues and cancerous cell lines. Conversely, miR-124-3p and miR-506-3p were down-regulated in liver cancer tissues and cell lines. The protein expression of SIRT1 was significantly declined in HepG2 and SMMC7721 cells after transfection with miR-124-3p or miR-506-3p mimics. miR-124-3p and miR-506-3p collaboratively caused a marked inhibition of liver cancer cell growth, migration and invasion, while the phenomena were neutralized by overexpression of SIRT1. In vivo experimental measurements also revealed that miR-124-3p and miR-506-3p synergistically inhibited SIRT1 protein expression and tumour growth in the nude-mouse transplanted tumour model. Conclusion: It was observed that miR-124-3p and miR-506-3p could cooperatively retard liver cancer cell growth via co-inhibiting SIRT1 protein expression.
Collapse
Affiliation(s)
- Huali Xiang
- Department of Health Management and Physical Examination, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, China
| | - Ming Luo
- Department of General Surgery, Jiangxi Children's Hospital, Nanchang, China
| | - Ping Hou
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhouqing Xiao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhihao Huang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qian Feng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Rongguiyi Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yong Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Linquan Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| |
Collapse
|
|
29
|
Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Mol Biol Rep 2021; 48:3695-3717. [PMID: 33893928 DOI: 10.1007/s11033-021-06334-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 04/02/2021] [Indexed: 12/22/2022]
Abstract
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer deaths in the world. The most common type of liver cancers is hepatocellular carcinoma (HCC). Autophagy is the cellular digestion of harmful components by sequestering the waste products into autophagosomes followed by lysosomal degradation for the maintenance of cellular homeostasis. The impairment of autophagy is highly associated with the development and progression of HCC although autophagy may be involved in tumour-suppressing cellular events. In regards to its protecting role, autophagy also shelters the cells from anoikis- a programmed cell death in anchorage-dependent cells detached from the surrounding extracellular matrix which facilitates metastasis in HCC. Liver cancer stem cells (LCSCs) have the ability for self-renewal and differentiation and are associated with the development and progression of HCC by regulating stemness, resistance and angiogenesis. Interestingly, autophagy is also known to regulate normal stem cells by promoting cellular survival and differentiation and maintaining cellular homeostasis. In this review, we discuss the basal autophagic mechanisms and double-faceted roles of autophagy as both tumour suppressor and tumour promoter in HCC, as well as its association with and contribution to self-renewal and differentiation of LCSCs.
Collapse
|
|
30
|
Longo M, Paolini E, Meroni M, Dongiovanni P. Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC. Int J Mol Sci 2021; 22:4173. [PMID: 33920670 PMCID: PMC8073183 DOI: 10.3390/ijms22084173] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver ("mitochondrial plasticity"). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic-lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.
Collapse
Affiliation(s)
- Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Francesco Sforza 35, 20122 Milano, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
| |
Collapse
|
|
31
|
Sivasudhan E, Blake N, Lu ZL, Meng J, Rong R. Dynamics of m6A RNA Methylome on the Hallmarks of Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:642443. [PMID: 33869193 PMCID: PMC8047153 DOI: 10.3389/fcell.2021.642443] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/23/2021] [Indexed: 12/19/2022] Open
Abstract
Epidemiological data consistently rank hepatocellular carcinoma (HCC) as one of the leading causes of cancer-related deaths worldwide, often posing severe economic burden on health care. While the molecular etiopathogenesis associated with genetic and epigenetic modifications has been extensively explored, the biological influence of the emerging field of epitranscriptomics and its associated aberrant RNA modifications on tumorigenesis is a largely unexplored territory with immense potential for discovering new therapeutic approaches. In particular, the underlying cellular mechanisms of different hallmarks of hepatocarcinogenesis that are governed by the complex dynamics of m6A RNA methylation demand further investigation. In this review, we reveal the up-to-date knowledge on the mechanistic and functional link between m6A RNA methylation and pathogenesis of HCC.
Collapse
Affiliation(s)
- Enakshi Sivasudhan
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China.,Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Neil Blake
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Zhi-Liang Lu
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China.,Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Jia Meng
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China.,Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Rong Rong
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China.,Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| |
Collapse
|
|
32
|
Ezhilarasan D, Lakshmi T, Subha M, Deepak Nallasamy V, Raghunandhakumar S. The ambiguous role of sirtuins in head and neck squamous cell carcinoma. Oral Dis 2021; 28:559-567. [PMID: 33570800 DOI: 10.1111/odi.13798] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 01/25/2021] [Accepted: 02/05/2021] [Indexed: 12/14/2022]
Abstract
Oral cancer is one of the most leading cancer responsible for significant morbidity and mortality. The sirtuins (SIRTs) are a family of class III histone deacetylases and are known to regulate a variety of molecular signaling associated with different cancer types including oral malignancies. SIRT1 acts as bifunctional in a variety of cancer. In oral cancer, SIRT1 seems to work as a tumor suppressor. The carcinogenic potential of SIRT1 is also reported in oral cancer, and hence, its role is still ambiguous. SIRT2 is also said to play a dual-faced role in different types of cancers. However, in oral cancer, SIRT2 is not studied and its role remains obscure. SIRT3 expression was positively correlated with oral malignancies. However, studies also showed the anti-cancer role of SIRT3 in oral cancer. SIRT7 loss was observed in oral cancer cells, while its overexpression caused the suppression of oral cancer cells proliferation, migration, and invasiveness. The role of other SIRTs in oral cancer was studied meagerly or reports not available. To date, only the roles of SIRT1, SIRT3, and SIRT7 have been reported in oral malignancies. Therefore, understanding the regulatory mechanisms employed by sirtuins to modulate oral cancer is important for developing potential anti-cancer therapeutic strategies.
Collapse
Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, the Blue Lab (Molecular Medicine and Toxicology) Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Thangavelu Lakshmi
- Department of Pharmacology, the Blue Lab (Molecular Medicine and Toxicology) Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Manoharan Subha
- Department of Oral Medicine and Radiology, Saveetha Dental College (SDC), Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Veeraiyan Deepak Nallasamy
- Department of Prosthodontics, Saveetha Dental College (SDC), Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Subramanian Raghunandhakumar
- Department of Pharmacology, the Blue Lab (Molecular Medicine and Toxicology) Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| |
Collapse
|
|
33
|
Patel MS, Mahmood S, Jung J, Rideout TC. Reprogramming of aerobic glycolysis in non-transformed mouse liver with pyruvate dehydrogenase complex deficiency. Physiol Rep 2021; 9:e14684. [PMID: 33400855 PMCID: PMC7785054 DOI: 10.14814/phy2.14684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 12/19/2022] Open
Abstract
The Pyruvate Dehydrogenase Complex (PDC), a key enzyme in glucose metabolism, catalyzes an irreversible oxidative decarboxylation reaction of pyruvate to acetyl‐CoA, linking the cytosolic glycolytic pathway to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Earlier we reported a down‐regulation of several key hepatic lipogenic enzymes and their upstream regulators in liver‐specific PDC‐deficient mouse (L‐PDCKO model by deleting the Pdha1 gene). In this study we investigated gene expression profiles of key glycolytic enzymes and other proteins that respond to various metabolic stresses in liver from L‐PDCKO mice. Transcripts of several, such as hexokinase 2, phosphoglycerate kinase 1, pyruvate kinase muscle‐type 2, and lactate dehydrogenase B as well as those for the nonglycolysis‐related proteins, CD‐36, C/EBP homologous protein, and peroxisome proliferator‐activated receptor γ, were up‐regulated in L‐PDCKO liver whereas hypoxia‐induced factor‐1α, pyruvate dehydrogenase kinase 1 and Sirtuin 1 transcripts were down‐regulated. The protein levels of pyruvate kinase muscle‐type 2 and lactate dehydrogenase B were increased whereas that of lactate dehydrogenase A was decreased in PDC‐deficient mouse liver. Analysis of endoplasmic reticulum and oxidative stress indicators suggests that the L‐PDCKO liver showed evidence of the former but not the latter. These findings indicate that (i) liver‐specific PDC deficiency is sufficient to induce “aerobic glycolysis characteristic” in mouse liver, and (ii) the mechanism(s) responsible for these changes appears distinct from that which induces the Warburg effect in some cancer cells.
Collapse
Affiliation(s)
- Mulchand S Patel
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Saleh Mahmood
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Jiwon Jung
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Todd C Rideout
- Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA
| |
Collapse
|
|
34
|
Ren R, Wang Z, Wu M, Wang H. Emerging Roles of SIRT1 in Alcoholic Liver Disease. Int J Biol Sci 2020; 16:3174-3183. [PMID: 33162823 PMCID: PMC7645991 DOI: 10.7150/ijbs.49535] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide with a wide spectrum of liver pathologies ranging from simple steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. It has been demonstrated that ALD is mediated in whole or in part by a central signaling molecule sirtuin 1 (SIRT1), a conserved class III histone deacetylase.SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, inhibiting hepatic inflammation, controlling hepatic fibrosis and mediating hepatocellular carcinoma in ALD. However, underlying molecular mechanisms are complex and remain incompletely understood. The aim of this review was to highlight the latest advances in understanding of SIRT1 regulatory mechanisms in ALD and discuss their unique potential role as novel therapeutic target for ALD treatment.
Collapse
Affiliation(s)
- Ruixue Ren
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Ziming Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Miaomiao Wu
- School of Pharmacy, Institute of Liver Diseases, Anhui Medical University, Hefei 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.,School of Pharmacy, Institute of Liver Diseases, Anhui Medical University, Hefei 230032, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, Anhui, China
| |
Collapse
|
|
35
|
Zhu X, Liu Y, Xu J, Cheng Z, Yu Y, Chu M, Lu X, Yuan W. miR-608 rs4919510 Polymorphism May Affect Susceptibility to Colorectal Cancer by Upregulating MRPL43 Expression. DNA Cell Biol 2020; 39:2017-2027. [PMID: 33147064 DOI: 10.1089/dna.2020.5689] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
There are many studies on the association between miR-608 rs4919510 polymorphism and susceptibility to colorectal cancer (CRC). However, the role of rs4919510 in CRC development and its underlying mechanism remain unclear. We first evaluated the gene that may be regulated by the variation of rs4919510 through a two-stage expression quantitative trait loci analysis and then compared the expression of that identified gene in CRC tissues and adjacent nontumor tissues. Next, methyl thiazolyl tetrazolium (MTT) assay, transwell assay, and flow cytometry analyses were performed to investigate the in vitro capacity of cell proliferation, migration, invasion, apoptosis, and cell cycle of CRC cells, respectively. Finally, through bioinformatics prediction, we contrasted the regulatory network and identified microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that could regulate the obtained gene. We found that the variant G allele of rs4919510 located in miR-608 was associated with a potentially increased expression of MRPL43 in colon tissues (p = 0.065). Moreover, the results of functional experiments suggested that knockdown of the MRPL43 gene could inhibit the growth of the CRC HCT-116 cell line and promote apoptosis. Additionally, the cell cycle of CRC HCT-116 cell line was significantly arrested at the G2 phase. Next, we obtained a competing endogenous RNA regulatory network of MRPL43 with 17 pairs of miRNAs-lncRNAs by bioinformatics prediction, out of which, survival analysis indicated that different expression levels of miR-193b-3p (p = 0.0269) and miR-194-3p (p = 0.0113) were associated with overall survival in CRC patients. The rs4919510 variant G allele in miR-608 may increase the proliferation, invasion, and migration ability and decrease the apoptosis of CRC HCT-116 cell line by upregulating the expression of MRPL43, ultimately may affect the risk of CRC. Moreover, miR-193b-3p and miR-194-3p that target MRPL43 may serve as potential predictive biomarkers of CRC survival.
Collapse
Affiliation(s)
- Xiaoqi Zhu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
| | - Yichen Liu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
| | - Jingsheng Xu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
| | - Zhounan Cheng
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
| | - Yuhui Yu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
| | - Minjie Chu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
| | - Xiao Lu
- Department of Oncology, Changshu No. 1 People's Hospital, Suzhou, China
| | - Weiyan Yuan
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| |
Collapse
|
|
36
|
Laaroussi H, Ding Y, Teng Y, Deschamps P, Vidal M, Yu P, Broussy S. Synthesis of indole inhibitors of silent information regulator 1 (SIRT1), and their evaluation as cytotoxic agents. Eur J Med Chem 2020; 202:112561. [PMID: 32711231 DOI: 10.1016/j.ejmech.2020.112561] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/09/2020] [Accepted: 06/09/2020] [Indexed: 11/16/2022]
Abstract
A series of achiral indole analogues of the selective sirtuin inhibitor EX-527 (a racemic, substituted 1,2,3,4 tetrahydrocarbazole) was designed to stabilize the bioactive conformation, and synthesized. These new indoles were evaluated against the isolated sirtuin enzymes SIRT1 and SIRT2, and against a panel of nine human cell lines. Structure-activity relationship studies demonstrated the influence of the substituent at position 3 of the indole. The most potent SIRT1 inhibitor 3h, bearing an isopropyl substituent, was as potent as EX-527, and more selective for SIRT1 over SIRT2. Compound 3g, bearing a benzyl substituent, inhibited both sirtuins at micromolar concentration and was more cytotoxic than EX-527 on several cancer cell lines.
Collapse
Affiliation(s)
- Hanna Laaroussi
- Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, F-75006, Paris, France
| | - Ying Ding
- China International Science and Technology, Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Yuou Teng
- China International Science and Technology, Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | | | - Michel Vidal
- Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, F-75006, Paris, France; Service Biologie Du Médicament, Toxicologie, AP-HP, Hôpital Cochin, F-75014, Paris, France
| | - Peng Yu
- China International Science and Technology, Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Sylvain Broussy
- Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, F-75006, Paris, France.
| |
Collapse
|
|
37
|
Rotelli MT, Refolo MG, Lippolis C, Cavallini A, Picciariello A, Piscitelli D, Altomare DF. The role of miRNA-133b and its target gene SIRT1 in FAP-derived desmoid tumor. Oncotarget 2020; 11:2484-2492. [PMID: 32655835 PMCID: PMC7335664 DOI: 10.18632/oncotarget.27622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/14/2020] [Indexed: 11/25/2022] Open
Abstract
Signaling pathways have a key role in driving the uncontrolled development of familial adenomatous polyposis (FAP)- associated and sporadic desmoid tumors (DTs). The relationship between the Wnt/b-catenin signaling pathway and DTs has been extensively studied, but no reliable biomarkers able to detect their histological subtype have been identified for the accurate diagnosis. In this study we studied the differences in miRNA expression between sporadic (20 patients) and FAP-associated DTs (7 patients) using microarray confirmed by quantitative PCR (qPCR). The analysis showed 19 dysregulated miRNAs. Among them miR-133b levels were significantly lower in FAP-associated DT than in sporadic DT. Therefore, two mRNAs, associated to miR-133b and β-catenin expression, the SIRT1 and ELAVL1were analyzed. The qPCR analysis showed that SIRT1 mRNA levels were significantly up-regulated in FAP-associated DT than in sporadic DT, whereas no differences in ELAVL1 expression was observed between these two DT types. In addition, a negative correlation was observed between miR-133b and SIRT1 in FAP-associated DTs, but not in sporadic DTs. The miR-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying progression of FAP-associated DT.
Collapse
Affiliation(s)
- Maria Teresa Rotelli
- Department of Emergency and Organ Transplantation (DETO), University of Bari "Aldo Moro", Bari, Italy
| | - Maria Grazia Refolo
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte, Bari, Italy
| | - Catia Lippolis
- Department of Emergency and Organ Transplantation (DETO), University of Bari "Aldo Moro", Bari, Italy
| | - Aldo Cavallini
- Surgical Unit, Department of Emergency and Organ Transplantation (DETO), University of Bari "Aldo Moro", Bari, Italy
| | - Arcangelo Picciariello
- Department of Emergency and Organ Transplantation (DETO), University of Bari "Aldo Moro", Bari, Italy
| | - Domenico Piscitelli
- Department of Emergency and Organ Transplantation (DETO), University of Bari "Aldo Moro", Bari, Italy
| | - Donato Francesco Altomare
- Department of Emergency and Organ Transplantation (DETO), University of Bari "Aldo Moro", Bari, Italy.,IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| |
Collapse
|
|
38
|
Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Updat 2020; 53:100715. [PMID: 32679188 DOI: 10.1016/j.drup.2020.100715] [Citation(s) in RCA: 304] [Impact Index Per Article: 60.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 05/29/2020] [Accepted: 06/07/2020] [Indexed: 12/11/2022]
Abstract
It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) are crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurtures tumor-initiating/cancer stem-like cells (CSCs), induces both EMT and MDR leading to tumor relapses. Pro-thrombotic microenvironment created by inflammatory cytokines and chemokines from TAMs, MDSCs and CAFs is also involved in EMT and MDR. MDSCs are the most common mediators of immunosuppression and are also involved in resistance to targeted therapies, e.g. BRAF inhibitors and oncolytic viruses-based therapies. Expansion of both cancer and stroma cells causes hypoxia by hypoxia-inducible transcription factors (e.g. HIF-1α) resulting in drug resistance. TME factors induce the expression of transcriptional EMT factors, MDR and metabolic adaptation of cancer cells. Promoters of several ATP-binding cassette (ABC) transporter genes contain binding sites for canonical EMT transcription factors, e.g. ZEB, TWIST and SNAIL. Changes in glycolysis, oxidative phosphorylation and autophagy during EMT also promote MDR. Conclusively, EMT signaling simultaneously increases MDR. Owing to the multifactorial nature of MDR, targeting one mechanism seems to be non-sufficient to overcome resistance. Targeting inflammatory processes by immune modulatory compounds such as mTOR inhibitors, demethylating agents, low-dosed histone deacetylase inhibitors may decrease MDR. Targeting EMT and metabolic adaptation by small molecular inhibitors might also reverse MDR. In this review, we summarize evidence for TME components as causative factors of EMT and anticancer drug resistance.
Collapse
|
|
39
|
Jiang W, Xia J, Xie S, Zou R, Pan S, Wang ZW, Assaraf YG, Zhu X. Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs. Drug Resist Updat 2020; 50:100683. [DOI: 10.1016/j.drup.2020.100683] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/18/2020] [Accepted: 02/21/2020] [Indexed: 12/11/2022]
|
|
40
|
Si X, Gao Z, Xu F, Zheng Y. SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma. Mol Carcinog 2019; 59:257-264. [PMID: 31883360 DOI: 10.1002/mc.23148] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/03/2019] [Accepted: 12/09/2019] [Indexed: 12/15/2022]
Abstract
Paclitaxel is the last choice for the treatment of advanced melanoma as a second-line chemotherapeutic agent, but there are still many cases of intrinsic resistance to paclitaxel in melanoma and the reasons that cause paclitaxel resistance remain unclear. Here, we identified that high expression of SRY-box transcription factor 2 (SOX2) and high ratio of side population (SP) cells reduced the sensitivity to paclitaxel in melanoma cells. The knockout and the induction of SOX2 completely depleted and significantly upregulated the ratios of melanoma SP cells, respectively. These data suggest that SOX2, a pluripotent transcription factor for inducing cancer stem cells in melanoma, is also sufficient and necessary for the induction of melanoma SP cells. ATP-binding cassette (ABC) subfamily C member 1 (ABCC1) is one of ABC transporters which causes SP cells to be resistance to chemotherapeutic agents by efficiently pumping drugs out of cells. The knockout and the induction of ABCC1 significantly increased and decreased the sensitivity of melanoma cells to paclitaxel. High expression of ABCC1 was identified in melanoma cell lines with high expression of SOX2 and in their SP cells. SOX2 was identified to induce ABCC1 transcription. Taken together, SOX2 upregulates SP cells and enhances their chemoresistant ability by increasing ABCC1 expression, which contributes to intrinsic resistance to paclitaxel in melanoma. Our findings will lead to new insights into melanoma biology and therapy resistance, and eventually to new therapeutic targets.
Collapse
Affiliation(s)
- Xiaoqiang Si
- Department of Plastic Surgery, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Zhengjun Gao
- Department of Plastic Surgery, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Feihua Xu
- Department of Labor and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Zheng
- Department of Ophthalmonogy, Gansu Provincial Hospital, Lanzhou, Gansu, China
| |
Collapse
|