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Abdelmaksoud NM, Abulsoud AI, Abdelghany TM, Elshaer SS, Rizk SM, Senousy MA, Maurice NW. Uncovering SIRT3 and SHMT2-dependent pathways as novel targets for apigenin in modulating colorectal cancer: In vitro and in vivo studies. Exp Cell Res 2024; 441:114150. [PMID: 38971519 DOI: 10.1016/j.yexcr.2024.114150] [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: 05/31/2024] [Revised: 06/29/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
Despite significant advances in the treatment of colorectal cancer (CRC), identification of novel targets and treatment options are imperative for improving its prognosis and survival rates. The mitochondrial SIRT3 and SHMT2 have key roles in metabolic reprogramming and cell proliferation. This study investigated the potential use of the natural product apigenin in CRC treatment employing both in vivo and in vitro models and explored the role of SIRT3 and SHMT2 in apigenin-induced CRC apoptosis. The role of SHMT2 in CRC patients' survival was verified using TCGA database. In vivo, apigenin treatment restored the normal colon appearance. On the molecular level, apigenin augmented the immunohistochemical expression of cleaved caspase-3 and attenuated SIRT3 and SHMT2 mRNA expression CRC patients with decreased SHMT2 expression had improved overall and disease-free survival rates. In vitro, apigenin reduced the cell viability in a time-dependent manner, induced G0/G1 cell cycle arrest, and increased the apoptotic cell population compared to the untreated control. Mechanistically, apigenin treatment mitigated the expression of SHMT2, SIRT3, and its upstream long intergenic noncoding RNA LINC01234 in CRC cells. Conclusively, apigenin induces caspase-3-dependent apoptosis in CRC through modulation of SIRT3-triggered mitochondrial pathway suggesting it as a promising therapeutic agent to improve patient outcomes.
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Affiliation(s)
- Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11823, Egypt; Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt.
| | - Tamer M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11884, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020, El Salam, 11785, Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, 11823, Egypt
| | - Sherine Maher Rizk
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt
| | - Nadine W Maurice
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
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2
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Lin G, Zhan F, Jin L, Liu G, Wei W. The association between methylmalonic acid, a biomarker of mitochondrial dysfunction, and risk of prostate cancer. Int Urol Nephrol 2024; 56:1879-1885. [PMID: 38280131 DOI: 10.1007/s11255-024-03944-7] [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: 11/09/2023] [Accepted: 01/02/2024] [Indexed: 01/29/2024]
Abstract
BACKGROUND The aim of the study was to investigate the association between methylmalonic acid (MMA), a biomarker of mitochondrial dysfunction, and the risk of prostate cancer (PCa). METHODS AND MATERIALS The relevant data were collected from the National Health and Nutrition Examination Survey (NHANES). Weighted univariable and multivariable logistic regression analyses were performed to investigate the association between MMA and risk of PCa. A stratified analysis was also carried out. The dose-response relationship was elucidated by conducting a restricted cubic spline function. RESULTS A total of 2451 participants were included, of which 95 were PCa participants. The fully-adjusted model 2 constructed by weighted multivariable logistic regression analysis showed that the risk of PCa decreased by 53% when every MMA unit was added [OR: 0.47 (0.22-1.00), P = 0.049]. And a decrease in PCa risk was associated with a higher MMA level in MMA subgroups [OR: 0.34 (0.15-0.82), P = 0.02]. The results from a stratified analysis showed that participants in subgroups of other race, BMI (> 30 kg/m2), smoking (former and now), and hypertension (yes), an increase in every MMA unit was linked to a decrease in PCa risk. MMA and the risk of PCa were negatively correlated in a linear manner. CONCLUSION It was discovered in the study that an increase in MMA level is connected to a decrease in PCa risk. The serum MMA level may be helpful in assessing PCa risk.
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Affiliation(s)
- Gaoteng Lin
- Department of Urology, The 900th, Hospital of Joint Logistic Support Force, Fuzhou, China
| | - Fangfang Zhan
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, Fujian, China
- Department of Rehabilitation Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, Fujian, China
| | - Lianchao Jin
- Department of Urology, Beijing Geriatric Hospital, Beijing, 100095, China
| | - Guizhong Liu
- Department of Urology, Tianjin Jinnan Hospital/Tianjin University Jinnan Hospital, Tianjin, 300350, China
| | - Wanqing Wei
- Department of Urology, Lianshui People's Hospital of Kangda College Affiliated to Nanjing Medical University, Huai'an, 223400, Jiangsu, China.
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Cordani M, Garufi A, Benedetti R, Tafani M, Aventaggiato M, D’Orazi G, Cirone M. Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions. Biomolecules 2024; 14:649. [PMID: 38927053 PMCID: PMC11201733 DOI: 10.3390/biom14060649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/24/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024] Open
Abstract
The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers.
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Affiliation(s)
- Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Alessia Garufi
- Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Rossella Benedetti
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
| | - Marco Tafani
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
| | - Michele Aventaggiato
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
| | - Gabriella D’Orazi
- Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
- Department of Neurosciences, Imaging and Clinical Sciences, University G. D’Annunzio, 00131 Chieti, Italy
| | - Mara Cirone
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
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4
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Senthilkumar P, Gogoi B, Dhan SS, Subramani R, Pushparaj C, Mahesh A. Improving therapeutic potential in breast cancer via histone deacetylase inhibitor loaded nanofibrils. Drug Dev Res 2024; 85:e22172. [PMID: 38488434 DOI: 10.1002/ddr.22172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/08/2024] [Accepted: 03/02/2024] [Indexed: 03/19/2024]
Abstract
Epigenetic modifications play a significant role in cancer progression, making them potential targets for therapy. Histone deacetylase inhibitors have shown promise in inhibiting cancer cell growth, including in breast cancer (BC). In this research, we examined the potential of using suberoyl anilide hydroxamic acid (SAHA)-loaded β-lg nanofibrils as a drug delivery system for triple-negative BC cell lines. We assessed their impact on cell cycle progression, apoptosis, levels of reactive oxygen species, and mitochondrial membrane potential in cancer cells. The combination of SAHA and β-lg nanofibrils demonstrated enhanced efficacy in inhibiting cell growth, inducing cell cycle arrest, and promoting apoptosis (43.78%) compared to SAHA alone (40.09%). Moreover, it effectively targeted cancer cells without promoting drug resistance while using a low concentration of the nanofibrils. These findings underscore the promising potential of nanofibril-based drug delivery systems for BC treatment.
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Affiliation(s)
- Praveetha Senthilkumar
- Department of Chemistry, PSGR Krishnammal College for Women, Coimbatore, Tamilnadu, India
| | - Bhaskar Gogoi
- Centre for Stem Cell and Cancer Genomics, AM Institute of BioScience, Coimbatore, Tamilnadu, India
| | - Swati Smita Dhan
- Centre for Stem Cell and Cancer Genomics, AM Institute of BioScience, Coimbatore, Tamilnadu, India
| | - Ramesh Subramani
- Department of Food Processing Technology & Management, PSGR Krishnammal College for Women, Coimbatore, Tamilnadu, India
| | - Charumathi Pushparaj
- Department of Zoology, PSGR Krishnammal College for Women, Coimbatore, Tamilnadu, India
| | - Ayyavu Mahesh
- Centre for Stem Cell and Cancer Genomics, AM Institute of BioScience, Coimbatore, Tamilnadu, India
- AMIOmics, Coimbatore, Tamilnadu, India
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5
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Xue J, Ge P, Wu Y. The prognosis and clinicopathological significance of histone deacetylase in hepatocellular carcinoma: a meta-analysis. Clin Exp Med 2023; 23:1515-1536. [PMID: 36342581 DOI: 10.1007/s10238-022-00934-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 10/26/2022] [Indexed: 11/09/2022]
Abstract
The value of the different types of HDACs (histone deacetylases) for HCC (hepatocellular carcinoma) prognosis and clinicopathological features is still controversial. Here, we performed a meta-analysis to investigate the possible role of different types of HDACs in HCC. Until October 28, 2021, we have searched the Embase, Cochrane, PubMed, Scopus, Web of Science (WOS), SinoMed, Chinese China National Knowledge Infrastructure (CNKI), Chinese WanFang, and Chinese Weipu databases and evaluated eligible studies according to the criteria. We used hazard ratio (HR) and 95% confidence interval (95% CI) to evaluate the prognostic effects of different types of HDACs on overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and used odds ratio (OR) and corresponding 95% CI to evaluate the significance of HDACs on clinicopathological characteristics. The I2 statistic and chi-square-based Q test were used to assess the heterogeneity. When the heterogeneity was significant, we conducted a subgroup analysis. In addition, Egger's test and funnel chart were used to assess publication bias. The high expression of class I HDACs was associated with poorer OS, DFS/RFS and differentiation, intrahepatic metastasis, tumor-node-metastasis (TNM), tumor number, tumor size, vascular invasion, and other poor clinicopathological characteristics. The high expression of class II HDACs was related to poor OS and multiple and larger tumors. After subgroup analysis, class II HDACs may also be related to worse TNM and Edmondson grading. The high expression of class III HDACs was related to poor OS, hepatitis B, liver cirrhosis, serum AFP, and vascular invasion. But it was more common in women and was related to single, smaller tumors. Type I, II, and III HDACs are associated with poor prognosis, and there are also correlations with some clinicopathological features, suggesting that different types of HDACs may be valuable biomarkers for HCC.
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Affiliation(s)
- Jiahao Xue
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, China
| | - Penglei Ge
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, China
| | - Yang Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, China.
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6
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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7
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Jin J, Bai L, Wang D, Ding W, Cao Z, Yan P, Li Y, Xi L, Wang Y, Zheng X, Wei H, Ding C, Wang Y. SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth. EMBO Rep 2023; 24:e56052. [PMID: 36896611 PMCID: PMC10157311 DOI: 10.15252/embr.202256052] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 01/30/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023] Open
Abstract
Lysine lactylation (Kla) is a recently discovered histone mark derived from metabolic lactate. The NAD+ -dependent deacetylase SIRT3, which can also catalyze removal of the lactyl moiety from lysine, is expressed at low levels in hepatocellular carcinoma (HCC) and has been suggested to be an HCC tumor suppressor. Here we report that SIRT3 can delactylate non-histone proteins and suppress HCC development. Using SILAC-based quantitative proteomics, we identify cyclin E2 (CCNE2) as one of the lactylated substrates of SIRT3 in HCC cells. Furthermore, our crystallographic study elucidates the mechanism of CCNE2 K348la delactylation by SIRT3. Our results further suggest that lactylated CCNE2 promotes HCC cell growth, while SIRT3 activation by Honokiol induces HCC cell apoptosis and prevents HCC outgrowth in vivo by regulating Kla levels of CCNE2. Together, our results establish a physiological function of SIRT3 as a delactylase that is important for suppressing HCC, and our structural data could be useful for the future design of activators.
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Affiliation(s)
- Jing Jin
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
| | - Lin Bai
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Dongyao Wang
- Division of Life Sciences and Medicine, Department of Hematology, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiChina
| | - Wei Ding
- Beijing National Laboratory for Condensed Matter Physics, Institute of PhysicsChinese Academy of SciencesBeijingChina
| | - Zhuoxian Cao
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Peidong Yan
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Yunjia Li
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Lulu Xi
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Yuxin Wang
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
| | - Xiaohu Zheng
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
| | - Chen Ding
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yi Wang
- Division of Life Sciences and Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHeifeiChina
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
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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.
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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
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9
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Podyacheva E, Toropova Y. The Role of NAD+, SIRTs Interactions in Stimulating and Counteracting Carcinogenesis. Int J Mol Sci 2023; 24:ijms24097925. [PMID: 37175631 PMCID: PMC10178434 DOI: 10.3390/ijms24097925] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The World Health Organization has identified oncological diseases as one of the most serious health concerns of the current century. Current research on oncogenesis is focused on the molecular mechanisms of energy-biochemical reprogramming in cancer cell metabolism, including processes contributing to the Warburg effect and the pro-oncogenic and anti-oncogenic roles of sirtuins (SIRTs) and poly-(ADP-ribose) polymerases (PARPs). However, a clear understanding of the interaction between NAD+, SIRTs in cancer development, as well as their effects on carcinogenesis, has not been established, and literature data vary greatly. This work aims to provide a summary and structure of the available information on NAD+, SIRTs interactions in both stimulating and countering carcinogenesis, and to discuss potential approaches for pharmacological modulation of these interactions to achieve an anticancer effect.
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Affiliation(s)
- Ekaterina Podyacheva
- Almazov National Medical Research Centre, Ministry of Health of the Russian Federation, 197341 Saint-Petersburg, Russia
| | - Yana Toropova
- Almazov National Medical Research Centre, Ministry of Health of the Russian Federation, 197341 Saint-Petersburg, Russia
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10
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Insights into Regulators of p53 Acetylation. Cells 2022; 11:cells11233825. [PMID: 36497084 PMCID: PMC9737083 DOI: 10.3390/cells11233825] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
The tumor suppressor p53 is a transcription factor that regulates the expression of dozens of target genes and diverse physiological processes. To precisely regulate the p53 network, p53 undergoes various post-translational modifications and alters the selectivity of target genes. Acetylation plays an essential role in cell fate determination through the activation of p53. Although the acetylation of p53 has been examined, the underlying regulatory mechanisms remain unclear and, thus, have attracted the interest of researchers. We herein discuss the role of acetylation in the p53 pathway, with a focus on p53 acetyltransferases and deacetylases. We also review recent findings on the regulators of these enzymes to understand the mode of p53 acetylation from a broader perspective.
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11
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Hai R, Yang D, Zheng F, Wang W, Han X, Bode AM, Luo X. The emerging roles of HDACs and their therapeutic implications in cancer. Eur J Pharmacol 2022; 931:175216. [PMID: 35988787 DOI: 10.1016/j.ejphar.2022.175216] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/03/2022] [Accepted: 08/12/2022] [Indexed: 12/25/2022]
Abstract
Deregulation of protein post-translational modifications is intensively involved in the etiology of diseases, including degenerative diseases, inflammatory injuries, and cancers. Acetylation is one of the most common post-translational modifications of proteins, and the acetylation levels are controlled by two mutually antagonistic enzyme families, histone acetyl transferases (HATs) and histone deacetylases (HDACs). HATs loosen the chromatin structure by neutralizing the positive charge of lysine residues of histones; whereas HDACs deacetylate certain histones, thus inhibiting gene transcription. Compared with HATs, HDACs have been more intensively studied, particularly regarding their clinical significance. HDACs extensively participate in the regulation of proliferation, migration, angiogenesis, immune escape, and therapeutic resistance of cancer cells, thus emerging as critical targets for clinical cancer therapy. Compared to HATs, inhibitors of HDAC have been clinically used for cancer treatment. Here, we enumerate and integratethe mechanisms of HDAC family members in tumorigenesis and cancer progression, and address the new and exciting therapeutic implications of single or combined HDAC inhibitor (HDACi) treatment.
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Affiliation(s)
- Rihan Hai
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Deyi Yang
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Feifei Zheng
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Weiqin Wang
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Xing Han
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China; Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China; Key Laboratory of Biological Nanotechnology of National Health Commission, Central South University, Changsha, Hunan, 410078, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078, China.
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12
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Yapryntseva MA, Maximchik PV, Zhivotovsky B, Gogvadze V. Mitochondrial sirtuin 3 and various cell death modalities. Front Cell Dev Biol 2022; 10:947357. [PMID: 35938164 PMCID: PMC9354933 DOI: 10.3389/fcell.2022.947357] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/05/2022] [Indexed: 11/13/2022] Open
Abstract
Sirtuin 3, a member of the mammalian sirtuin family of proteins, is involved in the regulation of multiple processes in cells. It is a major mitochondrial NAD+-dependent deacetylase with a broad range of functions, such as regulation of oxidative stress, reprogramming of tumor cell energy pathways, and metabolic homeostasis. One of the intriguing functions of sirtuin 3 is the regulation of mitochondrial outer membrane permeabilization, a key step in apoptosis initiation/progression. Moreover, sirtuin 3 is involved in the execution of various cell death modalities, which makes sirtuin 3 a possible regulator of crosstalk between them. This review is focused on the role of sirtuin 3 as a target for tumor cell elimination and how mitochondria and reactive oxygen species (ROS) are implicated in this process.
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Affiliation(s)
| | - Polina V. Maximchik
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Boris Zhivotovsky
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia
- Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden
| | - Vladimir Gogvadze
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia
- Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden
- *Correspondence: Vladimir Gogvadze,
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13
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Shi C, Jiao F, Wang Y, Chen Q, Wang L, Gong Z. SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Front Physiol 2022; 13:915193. [PMID: 35923224 PMCID: PMC9340259 DOI: 10.3389/fphys.2022.915193] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/29/2022] [Indexed: 11/28/2022] Open
Abstract
The purpose of the study was to explore the effects of SIRT3 inhibitor 3-TYP on acute liver failure (ALF) in mice and its underlying mechanism. The mice were treated with thioacetamide (TAA, 300 mg/kg) for inducing ALF model. 3-TYP (50 mg/kg) was administered 2 h prior to TAA. The liver histological changes were measured by HE staining. Blood samples were collected for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). MDA and GSH were used to evaluate the oxidative stress of liver. The expression levels of inflammatory cytokines (TNF-α and IL-1β) were measured by ELISA and Western blotting. The cell type expression of IL-1β in liver tissue was detected by immunofluorescent staining. The expression of SIRT3, MnSOD, ALDH2, MAPK, NF-κB, Nrf2/HO-1, p-elF2α/CHOP, and cleaved caspase 3 was determined by Western blotting. TUNEL staining was performed to detect the apoptosis cells of liver tissues. 3-TYP exacerbated the liver injury of ALF mice. 3-TYP increased the inflammatory responses and activation of MAPK and NF-κB pathways. In addition, 3-TYP administration enhanced the damage of oxidative stress, endoplasmic reticulum stress, and promoted hepatocyte apoptosis in ALF mice. 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Activation of SIRT3 could be a promising target for the treatment of ALF.
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Affiliation(s)
- Chunxia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fangzhou Jiao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Luwen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Zuojiong Gong,
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14
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Abdalla MS, El-Mahdy ESM, Mansour SZ, Elsonbaty SM, Amin MH. Regulation of Sirtuin-3 and ERK1/2/p38MAPK by the combination Ga nanoparticles/γ-radiation low dosage: an effective approach for treatment of hepatocellular carcinoma. J Genet Eng Biotechnol 2022; 20:93. [PMID: 35776276 PMCID: PMC9249962 DOI: 10.1186/s43141-022-00385-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 06/17/2022] [Indexed: 11/13/2022]
Abstract
Background Synthesized gallium nanoparticles synthesized by grape seed extract were characterized with spherical shape and size range less than100 nm, possessing the functional groups of the biological material. The purpose of this study is to evaluate gallium nanoparticles synthesized by grape seed extract, as an antitumor agent with low dose of γ-radiation against hepatocellular carcinoma in rats. Aim of work This work aimed to evaluate the antitumor effect of gallium nanoparticles synthesized (GaNPs) by grape seed extract and the co-binded treatment with low dose of γ-radiation on hepatocellular carcinoma in rats, through evaluating their effect on signaling pathways and tumor markers. Results Cytotoxic activity of GaNPs synthesized by grape seed extract was estimated by mediated cytotoxicity assay on HepG2 cell line that recorded IC50 of 388.8 μg/ml. To achieve these goals, eighty Wistar male rats (120−150 g) will be divided into eight groups, each of 10 rats. The animals are administered with diethylnitrosamine to induce hepatocellular carcinoma and then orally administered with GaNPs synthesized by grape seed extract (38.5 mg/kg) in combination with the exposure of the total body to a low dose of γ-radiation (0.5 Gy). The treatment modulated plasma vascular endothelial growth factor and alpha-fetoprotein. In addition, the immunoblotting results of nuclear factor-kappa beta showed a marked downregulation of extracellular signal-regulated kinase, mitogen-activated protein kinase, and c-Jun NH2-terminal kinase alongside, significantly elevating the level of Sirtuin-3 and caspase-3. Conclusions It can be concluded that the combined treatment with GaNPs synthesized by grape seed extract and low dose γ-radiation may have antineoplastic activity against hepatocarcinogenesis by inhibiting signal pathways extracellular signal-regulated kinase/mitogen-activated protein kinase/c-Jun NH2-terminal kinase and stimulating apoptotic protein.
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Affiliation(s)
- Mohga S Abdalla
- Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt
| | - El-Sayed M El-Mahdy
- Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt
| | - Somaya Z Mansour
- Department of Radiobiology, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Nasr City, Egypt
| | - Sawsan M Elsonbaty
- Department of Radiation Microbiology, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Nasr City, Egypt
| | - Menna H Amin
- Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt.
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15
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Ouyang S, Zhang Q, Lou L, Zhu K, Li Z, Liu P, Zhang X. The Double-Edged Sword of SIRT3 in Cancer and Its Therapeutic Applications. Front Pharmacol 2022; 13:871560. [PMID: 35571098 PMCID: PMC9092499 DOI: 10.3389/fphar.2022.871560] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Reprogramming of cellular energy metabolism is considered an emerging feature of cancer. Mitochondrial metabolism plays a crucial role in cancer cell proliferation, survival, and metastasis. As a major mitochondrial NAD+-dependent deacetylase, sirtuin3 (SIRT3) deacetylates and regulates the enzymes involved in regulating mitochondrial energy metabolism, including fatty acid oxidation, the Krebs cycle, and the respiratory chain to maintain metabolic homeostasis. In this article, we review the multiple roles of SIRT3 in various cancers, and systematically summarize the recent advances in the discovery of its activators and inhibitors. The roles of SIRT3 vary in different cancers and have cell- and tumor-type specificity. SIRT3 plays a unique function by mediating interactions between mitochondria and intracellular signaling. The critical functions of SIRT3 have renewed interest in the development of small molecule modulators that regulate its activity. Delineation of the underlying mechanism of SIRT3 as a critical regulator of cell metabolism and further characterization of the mitochondrial substrates of SIRT3 will deepen our understanding of the role of SIRT3 in tumorigenesis and progression and may provide novel therapeutic strategies for cancer targeting SIRT3.
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Affiliation(s)
- Shumin Ouyang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Qiyi Zhang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Linlin Lou
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Kai Zhu
- Innovation Practice Center, Changchun University of Chinese Medicine, Changchun, China
| | - Zeyu Li
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Peiqing Liu
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Xiaolei Zhang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
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16
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Hydroquinone destabilizes BIM mRNA through upregulation of p62 in chronic myeloid leukemia cells. Biochem Pharmacol 2022; 199:115017. [DOI: 10.1016/j.bcp.2022.115017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/19/2022] [Accepted: 03/21/2022] [Indexed: 11/21/2022]
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17
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Tubeimoside I Ameliorates Myocardial Ischemia-Reperfusion Injury through SIRT3-Dependent Regulation of Oxidative Stress and Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5577019. [PMID: 34795840 PMCID: PMC8595016 DOI: 10.1155/2021/5577019] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 09/13/2021] [Accepted: 10/23/2021] [Indexed: 12/31/2022]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is a phenomenon that reperfusion leads to irreversible damage to the myocardium and increases mortality in acute myocardial infarction (AMI) patients. There is no effective drug to treat MIRI. Tubeimoside I (TBM) is a triterpenoid saponin purified from Chinese traditional medicine tubeimu. In this study, 4 mg/kg TBM was given to mice intraperitoneally at 15 min after ischemia. And TBM treatment improved postischemic cardiac function, decreased infarct size, diminished lactate dehydrogenase release, ameliorated oxidative stress, and reduced apoptotic index. Notably, ischemia-reperfusion induced a significant decrease in cardiac SIRT3 expression and activity, while TBM treatment upregulated SIRT3's expression and activity. However, the cardioprotective effects of TBM were largely abolished by a SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). This suggests that SIRT3 plays an essential role in TBM's cardioprotective effects. In vitro, TBM also protected H9c2 cells against simulated ischemia/reperfusion (SIR) injury by attenuating oxidative stress and apoptosis, and siSIRT3 diminished its protective effects. Taken together, our results demonstrate for the first time that TBM protects against MIRI through SIRT3-dependent regulation of oxidative stress and apoptosis. TBM might be a potential drug candidate for MIRI treatment.
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18
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Broussochalcone A Induces Apoptosis in Human Renal Cancer Cells via ROS Level Elevation and Activation of FOXO3 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2800706. [PMID: 34745413 PMCID: PMC8566040 DOI: 10.1155/2021/2800706] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/01/2021] [Accepted: 10/11/2021] [Indexed: 11/18/2022]
Abstract
Broussochalcone A (BCA) is a chalcone compound extracted from the cortex of Broussonetiapapyrifera (L.) Ventenat that exerts various effects, such as potent antioxidant, antiplatelet, and anticancer effects. However, the effects of BCA against cancers have been seldom studied. This study is aimed at demonstrating the apoptotic mechanisms of BCA in A498 and ACHN cells, which are two types of human renal cancer cell lines. MTT, cell counting, and colony formation assays indicated that BCA treatment inhibited cell viability and cell growth. Further, cell cycle analysis revealed that BCA induced cell cycle arrest at the G2/M phase. Annexin V/PI staining and TUNEL assays were performed to determine the apoptotic effects and DNA fragmentation after treatment with BCA. Based on western blot analysis, BCA induced the upregulation of cleaved PARP, FOXO3, Bax, p21, p27, p53, phosphorylated p53 (ser15, ser20, and ser46), and active forms of caspase-3, caspase-7, and caspase-9 proteins, but downregulated the proforms of the proteins. The expression levels of pAkt, Bcl-2, and Bcl-xL were also found to be downregulated. Western blot analysis of nuclear fractionation results revealed that BCA induced the nuclear translocation of FOXO3, which might be induced by DNA damage owing to the accumulation of reactive oxygen species (ROS). Elevated intracellular ROS levels were also found following BCA treatment. Furthermore, DNA damage was detected after BCA treatment using a comet assay. The purpose of this study was to elucidate the apoptotic effects of BCA against renal cancer A498 and ACHN cells. Collectively, our study findings revealed that the apoptotic effects of BCA against human renal cancer cells occur via the elevation of ROS level and activation of the FOXO3 signaling pathway.
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Halasa M, Adamczuk K, Adamczuk G, Afshan S, Stepulak A, Cybulski M, Wawruszak A. Deacetylation of Transcription Factors in Carcinogenesis. Int J Mol Sci 2021; 22:11810. [PMID: 34769241 PMCID: PMC8583941 DOI: 10.3390/ijms222111810] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
Reversible Nε-lysine acetylation/deacetylation is one of the most common post-translational modifications (PTM) of histones and non-histone proteins that is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This epigenetic process is highly involved in carcinogenesis, affecting histone and non-histone proteins' properties and their biological functions. Some of the transcription factors, including tumor suppressors and oncoproteins, undergo this modification altering different cell signaling pathways. HDACs deacetylate their targets, which leads to either the upregulation or downregulation of proteins involved in the regulation of cell cycle and apoptosis, ultimately influencing tumor growth, invasion, and drug resistance. Therefore, epigenetic modifications are of great clinical importance and may constitute a new therapeutic target in cancer treatment. This review is aimed to present the significance of HDACs in carcinogenesis through their influence on functions of transcription factors, and therefore regulation of different signaling pathways, cancer progression, and metastasis.
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Affiliation(s)
- Marta Halasa
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Kamila Adamczuk
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Grzegorz Adamczuk
- Independent Medical Biology Unit, Medical University of Lublin, Kazimierza Jaczewskiego 8b St., 20-090 Lublin, Poland;
| | - Syeda Afshan
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland;
| | - Andrzej Stepulak
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Marek Cybulski
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Anna Wawruszak
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
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20
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Wawruszak A, Borkiewicz L, Okon E, Kukula-Koch W, Afshan S, Halasa M. Vorinostat (SAHA) and Breast Cancer: An Overview. Cancers (Basel) 2021; 13:4700. [PMID: 34572928 PMCID: PMC8468501 DOI: 10.3390/cancers13184700] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/12/2021] [Accepted: 09/15/2021] [Indexed: 02/07/2023] Open
Abstract
Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made, high toxicity to normal cells, serious side effects, and the occurrence of multi-drug resistance limit the effective therapy of BC patients. Therefore, new active agents which improve the effectiveness of currently used regimens are highly needed. This manuscript analyzes preclinical and clinical trials data of SAHA, applied individually or in combination with other anticancer agents, considering different histological subtypes of BC.
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Affiliation(s)
- Anna Wawruszak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (L.B.); (E.O.); (M.H.)
| | - Lidia Borkiewicz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (L.B.); (E.O.); (M.H.)
| | - Estera Okon
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (L.B.); (E.O.); (M.H.)
| | - Wirginia Kukula-Koch
- Department of Pharmacognosy, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Syeda Afshan
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20521 Turku, Finland;
| | - Marta Halasa
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (L.B.); (E.O.); (M.H.)
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21
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Jakoube P, Cutano V, González-Morena JM, Keckesova Z. Mitochondrial Tumor Suppressors-The Energetic Enemies of Tumor Progression. Cancer Res 2021; 81:4652-4667. [PMID: 34183354 PMCID: PMC9397617 DOI: 10.1158/0008-5472.can-21-0518] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/09/2021] [Accepted: 06/24/2021] [Indexed: 01/07/2023]
Abstract
Tumor suppressors represent a critical line of defense against tumorigenesis. Their mechanisms of action and the pathways they are involved in provide important insights into cancer progression, vulnerabilities, and treatment options. Although nuclear and cytosolic tumor suppressors have been extensively investigated, relatively little is known about tumor suppressors localized within the mitochondria. However, recent research has begun to uncover the roles of these important proteins in suppressing tumorigenesis. Here, we review this newly developing field and summarize available information on mitochondrial tumor suppressors.
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Affiliation(s)
- Pavel Jakoube
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Valentina Cutano
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Juan M. González-Morena
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Zuzana Keckesova
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Corresponding Author: Zuzana Keckesova, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo Namesti 2, Prague 16000, Czech Republic. Phone: 420-2201-83584; E-mail:
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22
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Zoraiz K, Attique M, Shahbaz S, Ahmed MW, Kayani MA, Mahjabeen I. Deregulation of mitochondrial sirtuins and OGG1-2a acts as a prognostic and diagnostic biomarker in leukemia. Future Oncol 2021; 17:3561-3577. [PMID: 34189942 DOI: 10.2217/fon-2020-1155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Purpose: The present study was planned to explore the expression variations of mitochondrial sirtuins and the mitochondrial DNA repair enzyme OGG1-2a in leukemia patients. Oxidative stress and deacetylation levels of leukemia patients were measured in the present study. Methods: A total of 200 leukemia patients along with 200 healthy controls were evaluated using quantitative PCR, 8OXOG assay and deacetylation assay. Results: Significant deregulation of SIRT3 (p < 0.0001), SIRT4 (p < 0.0001), SIRT5 (p < 0.0001), Ki-67 (p < 0.0001) and OGG1-2a (p < 0.0001) was detected in patients versus controls. Survival analysis showed that deregulation of said genes was associated with decreased survival of leukemia patients (SIRT3: p < 0.004; SIRT4: p < 0.0009; SIRT5: p < 0.0001; OGG1-2a: p < 0.03). Receiver operating characteristic curve analysis confirmed the diagnostic values of selected genes in leukemia patients. Levels of 8OXOG adducts were measured, and significantly increased 8OXOG adduct levels were observed in patients versus controls. Conclusion: These data suggest that deregulation of SIRT3, SIRT4, SIRT5 and OGG1-2a acts as a diagnostic and prognostic marker in leukemia.
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Affiliation(s)
- Kinza Zoraiz
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Muhammad Attique
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | | | - Malik Waqar Ahmed
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | | | - Ishrat Mahjabeen
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
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23
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Kratz EM, Sołkiewicz K, Kubis-Kubiak A, Piwowar A. Sirtuins as Important Factors in Pathological States and the Role of Their Molecular Activity Modulators. Int J Mol Sci 2021; 22:ijms22020630. [PMID: 33435263 PMCID: PMC7827102 DOI: 10.3390/ijms22020630] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
Sirtuins (SIRTs), enzymes from the family of NAD+-dependent histone deacetylases, play an important role in the functioning of the body at the cellular level and participate in many biochemical processes. The multi-directionality of SIRTs encourages scientists to undertake research aimed at understanding the mechanisms of their action and the influence that SIRTs have on the organism. At the same time, new substances are constantly being sought that can modulate the action of SIRTs. Extensive research on the expression of SIRTs in various pathological conditions suggests that regulation of their activity may have positive results in supporting the treatment of certain metabolic, neurodegenerative or cancer diseases or this connected with oxidative stress. Due to such a wide spectrum of activity, SIRTs may also be a prognostic markers of selected pathological conditions and prove helpful in assessing their progression, especially by modulating their activity. The article presents and discusses the activating or inhibiting impact of individual SIRTs modulators. The review also gathered selected currently available information on the expression of SIRTs in individual disease cases as well as the biological role that SIRTs play in the human organism, also in connection with oxidative stress condition, taking into account the progress of knowledge about SIRTs over the years, with particular reference to the latest research results.
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Affiliation(s)
- Ewa Maria Kratz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
- Correspondence: ; Tel.: +48-(71)-784-01-52
| | - Katarzyna Sołkiewicz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Adriana Kubis-Kubiak
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (A.K.-K.); (A.P.)
| | - Agnieszka Piwowar
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (A.K.-K.); (A.P.)
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Vadlakonda L, Indracanti M, Kalangi SK, Gayatri BM, Naidu NG, Reddy ABM. The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer. J Diabetes Metab Disord 2020; 19:1731-1775. [PMID: 33520860 DOI: 10.1007/s40200-020-00566-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
Purpose Re-examine the current metabolic models. Methods Review of literature and gene networks. Results Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.
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Affiliation(s)
| | - Meera Indracanti
- Institute of Biotechnology, University of Gondar, Gondar, Ethiopia
| | - Suresh K Kalangi
- Amity Stem Cell Institute, Amity University Haryana, Amity Education Valley Pachgaon, Manesar, Gurugram, HR 122413 India
| | - B Meher Gayatri
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
| | - Navya G Naidu
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
| | - Aramati B M Reddy
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
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Kenny TC, Craig AJ, Villanueva A, Germain D. Mitohormesis Primes Tumor Invasion and Metastasis. Cell Rep 2020; 27:2292-2303.e6. [PMID: 31116976 PMCID: PMC6579120 DOI: 10.1016/j.celrep.2019.04.095] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 03/19/2019] [Accepted: 04/22/2019] [Indexed: 12/31/2022] Open
Abstract
Moderate mitochondrial stress can lead to persistent activation of cytoprotective mechanisms - a phenomenon termed mitohormesis. Here, we show that mitohormesis primes a subpopulation of cancer cells to basally upregulate mitochondrial stress responses, such as the mitochondrial unfolded protein response (UPRmt) providing an adaptive metastatic advantage. In this subpopulation, UPRmt activation persists in the absence of stress, resulting in reduced oxidative stress indicative of mitohormesis. Mechanistically, we showed that the SIRT3 axis of UPRmt is necessary for invasion and metastasis. In breast cancer patients, a 7-gene UPRmt signature demonstrated that UPRmt-HIGH patients have significantly worse clinical outcomes, including metastasis. Transcriptomic analyses revealed that UPRmt-HIGH patients have expression profiles characterized by metastatic programs and the cytoprotective outcomes of mitohormesis. While mitohormesis is associated with health and longevity in non-pathological settings, these results indicate that it is perniciously used by cancer cells to promote tumor progression.
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Affiliation(s)
- Timothy C Kenny
- Tisch Cancer Institute, Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amanda J Craig
- Tisch Cancer Institute, Department of Medicine, Division of Liver Diseases, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Augusto Villanueva
- Tisch Cancer Institute, Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Department of Medicine, Division of Liver Diseases, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Doris Germain
- Tisch Cancer Institute, Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Cao H, Chen X, Wang Z, Wang L, Xia Q, Zhang W. The role of MDM2-p53 axis dysfunction in the hepatocellular carcinoma transformation. Cell Death Discov 2020; 6:53. [PMID: 32595984 PMCID: PMC7305227 DOI: 10.1038/s41420-020-0287-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/24/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4+T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.
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Affiliation(s)
- Hui Cao
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Xiaosong Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Zhijun Wang
- Department of Traditional Chinese Medicine, Putuo People’s Hospital Affiliated to Tongji University, Shanghai, China
| | - Lei Wang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Wei Zhang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
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Sirt3 Exerts Its Tumor-Suppressive Role by Increasing p53 and Attenuating Response to Estrogen in MCF-7 Cells. Antioxidants (Basel) 2020; 9:antiox9040294. [PMID: 32244715 PMCID: PMC7222218 DOI: 10.3390/antiox9040294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/21/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Estrogen (E2) is a major risk factor for the initiation and progression of malignancy in estrogen receptor (ER) positive breast cancers, whereas sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, has the inhibitory effect on the tumorigenic properties of ER positive MCF-7 breast cancer cells. Since it is unclear if this effect is mediated through the estrogen receptor alpha (ERα) signaling pathway, in this study, we aimed to determine if the tumor-suppressive function of Sirt3 in MCF-7 cells interferes with their response to E2. Although we found that Sirt3 improves the antioxidative response and mitochondrial fitness of the MCF-7 cells, it also increases DNA damage along with p53, AIF, and ERα expression. Moreover, Sirt3 desensitizes cells to the proliferative effect of E2, affects p53 by disruption of the ERα–p53 interaction, and decreases proliferation, colony formation, and migration of the cells. Our observations indicate that these tumor-suppressive effects of Sirt3 could be reversed by E2 treatment only to a limited extent which is not sufficient to recover the tumorigenic properties of the MCF-7 cells. This study provides new and interesting insights with respect to the functional role of Sirt3 in the E2-dependent breast cancers.
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Jin T, Wang C, Tian Y, Dai C, Zhu Y, Xu F. Mitochondrial metabolic reprogramming: An important player in liver cancer progression. Cancer Lett 2019; 470:197-203. [PMID: 31783085 DOI: 10.1016/j.canlet.2019.11.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 11/15/2019] [Accepted: 11/20/2019] [Indexed: 12/12/2022]
Abstract
Mitochondria are known as essential biosynthetic, bioenergetic and signaling organelles, and play a critical role in cell differentiation, proliferation, and death. Nowadays, cancer is emergingly considered as a mitochondrial metabolic disease. Mitochondria also play an essential role in liver carcinogenesis. Liver cells are highly regenerative and require high energy. For that reason, a large number of mitochondria are present and functional in liver cells. Abnormalities in mitochondrial metabolism in human liver are known to be one of the carcinogenic factors. Interestingly, immune checkpoints regulate mitochondrial metabolic energetics of the tumor, the tumor microenvironment, as well as the tumor-specific immune response. This regulation forms a positive loop between the metabolic reprogramming of both cancer cells and immune cells. In this review, we discuss the evidence and mechanisms that mitochondria interplay with immune checkpoints to influence different steps of oncogenesis, as well as the potential of mitochondria as therapeutic targets for liver cancer therapy.
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Affiliation(s)
- Tianqiang Jin
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Chao Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China; Department of Surgery, Northeast International Hospital, Shenyang, 110623, China
| | - Yu Tian
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Chaoliu Dai
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yuwen Zhu
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Feng Xu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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29
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Patra S, Panigrahi DP, Praharaj PP, Bhol CS, Mahapatra KK, Mishra SR, Behera BP, Jena M, Bhutia SK. Dysregulation of histone deacetylases in carcinogenesis and tumor progression: a possible link to apoptosis and autophagy. Cell Mol Life Sci 2019; 76:3263-3282. [PMID: 30982077 PMCID: PMC11105585 DOI: 10.1007/s00018-019-03098-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/25/2019] [Accepted: 04/08/2019] [Indexed: 02/08/2023]
Abstract
Dysregulation of the epigenome and constitutional epimutation lead to aberrant expression of the genes, which regulate cancer initiation and progression. Histone deacetylases (HDACs), which are highly conserved in yeast to humans, are known to regulate numerous proteins involved in the transcriptional regulation of chromatin structures, apoptosis, autophagy, and mitophagy. In addition, a non-permissive chromatin conformation is created by HDACs, preventing the transcription of the genes encoding the proteins associated with tumorigenesis. Recently, an expanding perspective has been reported from the clinical trials with HDACis (HDAC inhibitors), which has emerged as a determining target for the study of the detailed mechanisms underlying cancer progression. Therefore, the present review focuses on the comprehensive lucubration of post-translational modifications and the molecular mechanisms through which HDACs alter the ambiguities associated with epigenome, with particular insights into the initiation, progression, and regulation of cancer.
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Affiliation(s)
- Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Debasna P Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Prakash P Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Chandra S Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Kewal K Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Soumya R Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Bishnu P Behera
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Mrutyunjay Jena
- PG Department of Botany, Berhampur University, Brahmapur, 760007, India
| | - Sujit K Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India.
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30
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p53 at the Crossroads between Different Types of HDAC Inhibitor-Mediated Cancer Cell Death. Int J Mol Sci 2019; 20:ijms20102415. [PMID: 31096697 PMCID: PMC6567317 DOI: 10.3390/ijms20102415] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/06/2019] [Accepted: 05/13/2019] [Indexed: 12/19/2022] Open
Abstract
Cancer is a complex genetic and epigenetic-based disease that has developed an armada of mechanisms to escape cell death. The deregulation of apoptosis and autophagy, which are basic processes essential for normal cellular activity, are commonly encountered during the development of human tumors. In order to assist the cancer cell in defeating the imbalance between cell growth and cell death, histone deacetylase inhibitors (HDACi) have been employed to reverse epigenetically deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase- and deacetylase-mediated acetylation of both histone and non-histone proteins, and thereby exert a wide array of HDACi-stimulated cytotoxic effects. Key determinants of HDACi lethality that interfere with cellular growth in a multitude of tumor cells are apoptosis and autophagy, which are either mutually exclusive or activated in combination. Here, we compile known molecular signals and pathways involved in the HDACi-triggered induction of apoptosis and autophagy. Currently, the factors that determine the mode of HDACi-elicited cell death are mostly unclear. Correspondingly, we also summarized as yet established intertwined mechanisms, in particular with respect to the oncogenic tumor suppressor protein p53, that drive the interplay between apoptosis and autophagy in response to HDACi. In this context, we also note the significance to determine the presence of functional p53 protein levels in the cancer cell. The confirmation of the context-dependent function of autophagy will pave the way to improve the benefit from HDACi-mediated cancer treatment.
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31
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De Matteis S, Scarpi E, Granato AM, Vespasiani-Gentilucci U, La Barba G, Foschi FG, Bandini E, Ghetti M, Marisi G, Cravero P, Gramantieri L, Cucchetti A, Ercolani G, Santini D, Frassineti GL, Faloppi L, Scartozzi M, Cascinu S, Casadei-Gardini A. Role of SIRT-3, p-mTOR and HIF-1α in Hepatocellular Carcinoma Patients Affected by Metabolic Dysfunctions and in Chronic Treatment with Metformin. Int J Mol Sci 2019; 20:ijms20061503. [PMID: 30917505 PMCID: PMC6470641 DOI: 10.3390/ijms20061503] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/13/2019] [Accepted: 03/22/2019] [Indexed: 12/17/2022] Open
Abstract
The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1α) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1α expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1α as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC.
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Affiliation(s)
- Serena De Matteis
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Emanuela Scarpi
- Biostatistics and Clinical Trials Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Anna Maria Granato
- Immunotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Umberto Vespasiani-Gentilucci
- Interdisciplinary Center for Biomedical Research (CIR), Laboratory of Internal Medicine and Hepatology, Campus Bio-Medico University, 00128 Rome, Italy.
| | - Giuliano La Barba
- Department of General Surgery, Morgagni-Pierantoni Hospital, 47121 Forlì, Italy.
| | | | - Erika Bandini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Martina Ghetti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Paola Cravero
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Laura Gramantieri
- Center for Applied Biomedical Research (CRBa), St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy.
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy.
| | - Daniele Santini
- Medical Oncology Unit, Campus Biomedico University, 00128 Rome, Italy.
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Luca Faloppi
- Medical Oncology, University Hospital of Cagliari, 09124 Cagliari, Italy.
| | - Mario Scartozzi
- Medical Oncology, University Hospital of Cagliari, 09124 Cagliari, Italy.
| | - Stefano Cascinu
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, 41122 Modena, Italy.
| | - Andrea Casadei-Gardini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, 41122 Modena, Italy.
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Zhao J, Gray SG, Greene CM, Lawless MW. Unmasking the pathological and therapeutic potential of histone deacetylases for liver cancer. Expert Rev Gastroenterol Hepatol 2019; 13:247-256. [PMID: 30791763 DOI: 10.1080/17474124.2019.1568870] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, currently ranking as one of the highest neoplastic-related mortalities in the world. Due to the difficulty in early diagnosis and lack of effective treatment options, the 5-year survival rate of HCC remains extremely low. Histone deacetylation is one of the most important epigenetic mechanisms, regulating cellular events such as differentiation, proliferation and cell cycle. Histone deacetylases (HDACs), the chief mediators of this epigenetic mechanism, are often aberrantly expressed in various tumours including HCC. Areas covered: This review focuses on the most up-to-date findings of HDACs and their associated molecular mechanisms in HCC onset and progression. In addition, a potential network between HDACs and non-coding RNAs including microRNAs and long noncoding RNAs underlying hepatocarcinogenesis is considered. Expert opinion: Unmasking the role of HDACs and their association with HCC pathogenesis could have implications for future personalized therapeutic and diagnostic targeting.
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Affiliation(s)
- Jun Zhao
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
| | - Steven G Gray
- b Department of Clinical Medicine , Trinity Centre for Health Sciences, Trinity Translational Medicine Institute, St. James's Hospital & Trinity College , Dublin , Ireland
| | - Catherine M Greene
- c Clinical Microbiology , Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin , Ireland
| | - Matthew W Lawless
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
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SIRT3 a Major Player in Attenuation of Hepatic Ischemia-Reperfusion Injury by Reducing ROS via Its Downstream Mediators: SOD2, CYP-D, and HIF-1 α. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:2976957. [PMID: 30538800 PMCID: PMC6258096 DOI: 10.1155/2018/2976957] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 09/30/2018] [Accepted: 10/08/2018] [Indexed: 12/14/2022]
Abstract
Reactive oxygen species (ROS) production in hepatic ischemia-reperfusion injury (IRI) is a complex process where multiple cellular and molecular pathways are involved. Few of those molecular pathways are under the direct influence of SIRT3 and its downstream mediators. SIRT3 plays a major role in the mechanism of IRI, and its activation has been shown to attenuate the deleterious effect of ROS during IRI via SOD2-, CYP-D-, and HIF-1α-mediated pathways. The objective of this review is to analyze the current knowledge on SIRT3 and its downstream mediators: SOD2, CYP-D, and HIF-1α, and their role in IRI. For the references of this review article, we have searched the bibliographic databases of PubMed, Web of Science databases, MEDLINE, and EMBASE with the headings "SIRT3," "SOD2," "CYP-D," "HIF-1α," and "liver IRI." Priority was given to recent experimental articles that provide information on ROS modulation by these proteins. All the recent advancement demonstrates that activation of SIRT3 can suppress ROS production during IRI through various pathways and few of those are via SOD2, CYP-D, and HIF-1α. This effect can improve the quality of the remnant liver following resection as well as a transplanted liver. More research is warranted to disclose its role in IRI attenuation via this pathway.
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Hernández-López R, Torrens-Mas M, Pons DG, Company MM, Falcó E, Fernández T, Ibarra de la Rosa JM, Sastre-Serra J, Oliver J, Roca P. Non-tumor adjacent tissue of advanced stage from CRC shows activated antioxidant response. Free Radic Biol Med 2018; 126:249-258. [PMID: 30130568 DOI: 10.1016/j.freeradbiomed.2018.08.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 08/16/2018] [Accepted: 08/17/2018] [Indexed: 12/30/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of malignant cancer-related morbidity and mortality, with a higher incidence in developed countries and a high mortality rate mainly attributable to metastases. The aim of the present study was to determine the metabolic adaptations related to oxidative stress in tumor tissue from advanced stages (III and IV) of CRC and whether they could be used as potential biomarkers for clinical applications. To tackle this aim, we have analyzed the protein expression levels related to oxidative stress and the enzymatic activities of MnSOD and catalase, comparing samples of non-tumor adjacent tissue and tumor tissue of CRC patients in stages III and IV. The results showed no differences between stage III and IV in tumor tissues for any of the proteins studied. However, some differences were found between samples of non-tumor adjacent tissue and tumor tissue for some of the antioxidant enzymes. Overwhelmingly, the greatest differences were detected when comparing samples of non-tumor adjacent tissue from stage III and stage IV. To the best of our knowledge, this is the first study where differences between the non-tumor adjacent tissues of CRC patients from different cancer stages were determined. This study suggests that the parameters analyzed should be evaluated as biomarkers for the evolution of CRC. Furthermore, tumor tissue status should not be of sole importance for the prognosis of CRC, as the non-tumor adjacent tissues could also merit consideration.
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Affiliation(s)
- Reyniel Hernández-López
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d´Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, E-07122 Palma de Mallorca, Illes Balears, Spain; Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain
| | - Margalida Torrens-Mas
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d´Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, E-07122 Palma de Mallorca, Illes Balears, Spain; Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain
| | - Daniel G Pons
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d´Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, E-07122 Palma de Mallorca, Illes Balears, Spain; Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain
| | - Maria M Company
- Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Clinica Rotger, 07012 Palma de Mallorca, Islas Baleares, Spain
| | - Esther Falcó
- Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Hospital Son Llatzer, 07198 Palma de Mallorca, Illes Balears, Spain
| | - Teresa Fernández
- Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Hospital Son Llatzer, 07198 Palma de Mallorca, Illes Balears, Spain
| | - Javier M Ibarra de la Rosa
- Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Hospital Son Llatzer, 07198 Palma de Mallorca, Illes Balears, Spain
| | - Jorge Sastre-Serra
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d´Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, E-07122 Palma de Mallorca, Illes Balears, Spain; Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain
| | - Jordi Oliver
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d´Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, E-07122 Palma de Mallorca, Illes Balears, Spain; Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain.
| | - Pilar Roca
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d´Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, E-07122 Palma de Mallorca, Illes Balears, Spain; Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, edificio S, E-07120 Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain
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Feng L, Allen TK, Marinello WP, Murtha AP. Roles of Progesterone Receptor Membrane Component 1 in Oxidative Stress-Induced Aging in Chorion Cells. Reprod Sci 2018; 26:394-403. [PMID: 29783884 DOI: 10.1177/1933719118776790] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Oxidative stress-mediated fetal membrane cell aging is activated prematurely in preterm premature rupture of membranes (PPROMs). The mechanism of this phenomenon is largely understudied. Progesterone receptor membrane component 1 (PGRMC1) has been recognized as a potential protective component for maintaining fetal membrane integrity and healthy pregnancies. We aimed to investigate the effects of oxidative stress (represented by hydrogen peroxide [H2O2]) on fetal membrane and chorion cell senescence, p38 mitogen-activated protein kinase (MAPK) phosphorylation, and sirtuin 3 (SIRT3) and to examine the roles of PGRMC1 in these effects. METHODS Following serum starvation for 24 hours, full-thickness fetal membrane explants and primary chorion cells were treated with H2O2 at 100, 300, and 500 µM for 24 hours. Cells were fixed for cell senescence-associated β-galactosidase assay. Cell lysates were harvested for quantitive reverse transcription polymerase chain reaction to quantify SIRT3 messenger RNA. Cell lysates were harvested for Western blot to semi-quantify SIRT3 protein and p38 MAPK phosphorylation levels, respectively. To examine the role of PGRMC1, primary chorion cells underwent the same treatment mentioned above following PGRMC1 knockdown using validated PGRMC1-specific small-interfering RNA. RESULTS Hydrogen peroxide significantly induced cell senescence and p38 MAPK phosphorylation, and it significantly decreased SIRT3 expression in full-thickness fetal membrane explants and chorion cells. These effects were enhanced by PGRMC1 knockdown. DISCUSSION This study further demonstrated that oxidative stress-induced cell aging is one of the mechanisms of PPROM and PGRMC1 acts as a protective element for maintaining fetal membrane integrity by inhibiting oxidative stress-induced chorion cell aging.
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Affiliation(s)
- Liping Feng
- 1 Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA.,2 Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Terrence K Allen
- 3 Department of Anesthesiology, Duke University, Durham, NC, USA
| | | | - Amy P Murtha
- 1 Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA
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Xiong Y, Wang L, Wang S, Wang M, Zhao J, Zhang Z, Li X, Jia L, Han Y. SIRT3 deacetylates and promotes degradation of P53 in PTEN-defective non-small cell lung cancer. J Cancer Res Clin Oncol 2018; 144:189-198. [PMID: 29103158 DOI: 10.1007/s00432-017-2537-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 10/24/2017] [Indexed: 12/18/2022]
Abstract
PURPOSE In non-small cell lung cancer (NSCLC), success of targeted therapy has promoted researches explicitly orientated based on genetic background. Although PTEN deficiency is common in NSCLC, carcinogenesis about such genetic type has not been fully explored. Here, we have found that classical tumor suppressor P53 could be modulated by deacetylase sirtuin-3 (SIRT3) depending on the PTEN condition in NSCLC, which may be a novel breakpoint for handling PTEN deficiency NSCLC. METHODS First, we examined SIRT3 and P53 expression files in PTEN-deficient NSCLC clinical samples and investigated their correlation. Second, we built SIRT3 high or low expression models in different PTEN conditions by plasmid overexpression or si-RNA interference in NSCLC cell lines and explored the effect of SIRT3 upon P53. Furthermore, we investigated the influence of SIRT3 upon the ubiquitin-proteasome dependent degradation pathway of P53 in PTEN-deficient NSCLC cell lines. Finally, we probed into the deacetylation modification of P53 via SIRT3. RESULTS We found that SIRT3 expression was strongly positive and P53 expression was almost negative in PTEN-deficient NSCLC clinical samples. Further, we demonstrated that SIRT3 promoted degradation of P53 in PTEN-deficient NSCLC cell lines via the ubiquitin-proteasome pathway. Finally, we demonstrated that SIRT3 could deacetylate P53 at lysines 320 and 382, which may account for the observed degradation of P53 in PTEN-deficient tumor cells. CONCLUSIONS We have identified a novel mechanism by which P53 was inactivated via SIRT3 in PTEN-deficient cells. This may shed light on the mechanisms underlying the malignancy of PTEN-deficient NSCLC.
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Affiliation(s)
- Yanlu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
| | - Lei Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, China
| | - Shan Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, China
| | - Mingxing Wang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
| | - Zhipei Zhang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
| | - Xiaofei Li
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, China.
| | - Yong Han
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China.
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Mitochondrial energy metabolism and signalling in human glioblastoma cell lines with different PTEN gene status. J Bioenerg Biomembr 2017; 50:33-52. [PMID: 29209894 DOI: 10.1007/s10863-017-9737-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 11/27/2017] [Indexed: 12/12/2022]
Abstract
Glioblastomas epidemiology and aggressiveness demand for a well characterization of biochemical mechanisms of the cells. The discovery of oxidative tumours related to chemoresistance is changing the prevalent view of dysfunctional mitochondria in cancer cells. Thus, glioblastomas metabolism is now an area of intense research, wherein was documented a high heterogeneity in energy metabolism and in particular in mitochondrial OxPhos. We report results gained by investigating mitochondrial OxPhos and bioenergetics, in a model of three human glioblastoma cell lines characterized by a different PTEN gene status. Functional data are analysed in relation to the expression levels of some main transcription factors and signalling proteins, which can be involved in the regulation of mitochondrial biogenesis and activity. Collectively, our observations indicate for the three cell lines a similar bioenergetic phenotype maintaining a certain degree of mitochondrial oxidative activity, with some difference for PTEN-wild type SF767 cells respect to PTEN-deleted A172 and U87MG characterized by a loss-of-function point mutation of PTEN. SF767 has lower ATP content and higher ADP/ATP ratio, higher AMPK activating-phosphorylation evoking energy impairment, higher OxPhos complexes and PGC1α-Sirt3-p53 protein abundance, in line with a higher respiration. Finally, SF767 shows a similar mitochondrial energy supply, but higher non-phosphorylating respiration linked to dissipation of protonmotive force. Intriguingly, it is now widely accepted that a regulated mitochondrial proton leak attenuate ROS generation and in tumours may be at the base of pro-survival advantage and chemoresistance.
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Huang S, Chen X, Zheng J, Huang Y, Song L, Yin Y, Xiong J. Low SIRT3 expression contributes to tumor progression, development and poor prognosis in human pancreatic carcinoma. Pathol Res Pract 2017; 213:1419-1423. [PMID: 28867266 DOI: 10.1016/j.prp.2017.07.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 06/25/2017] [Accepted: 07/19/2017] [Indexed: 01/21/2023]
Abstract
SIRT3, an important mitochondrial protein, may act as either an oncogene or tumor suppressor depending on the tumor-type. The aim of this study was to investigate the expression of SIRT3 in pancreatic carcinoma (PC) and its clinical association in PC patients. Immunohistochemistry was adopted to investigate the expression of SIRT3 in cancer and corrresponding adjacent non-cancer tissues across 79 patients with PC. The log-rank test and Cox hazard model were used to estimate the relationship between SIRT3 expression and prognosis. The staining results revealed that SIRT3 negative expression was more common in cancer tissues than in adjacent non-cancer tissues (P<0.001). Chi-square tests indicated that the expression of SIRT3 correlated with T status (p<0.001) and tumor stage (p=0.013). Kaplan-Meier analysis showed that negative SIRT3 expression is linked to a poor prognosis in PC patients. Multivariate analysis identified SIRT3 expression as an independent predictor for PC outcome both in the whole cohort and several subgroups of PC patients. Our results indicate that down-regulated SIRT3 may contribute to tumor progression and gloomy prognosis in PC patients and may sever as a novel prognostic marker.
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Affiliation(s)
- Shanshan Huang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Jiangxi, China
| | - Xiong Chen
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Jiawei Zheng
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Yufang Huang
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Li Song
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Yin Yin
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Medical College Xiamen University, Xiamen, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Jiangxi, China.
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The Expression and Related Clinical Significance of SIRT3 in Non-Small-Cell Lung Cancer. DISEASE MARKERS 2017; 2017:8241953. [PMID: 28947845 PMCID: PMC5602652 DOI: 10.1155/2017/8241953] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 07/27/2017] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To examine the relationship between the Sirtuin-3 (SIRT3) expression and the clinical indicators/prognosis of patients with non-small-cell lung cancer (NSCLC). METHODS The mRNA level of SIRT3 was detected by real-time PCR, while the protein level was detected by Western blot and immunohistochemical staining. SPSS 16.0 software was used for statistical analysis. RESULTS The expression of SIRT3 was significantly higher in NSCLC tissue than in adjacent tissue. The SIRT3 level was correlated significantly with lymph node metastasis and clinical stage of NSCLC patients. Moreover, univariate analysis showed that the expression of SIRT3, tumor size, lymph node metastasis, degree of differentiation, and clinical stage were correlated with the prognosis of NSCLC patients. Multivariate analysis demonstrated that lymph node metastasis, the tumor size, and SIRT3 expression were independent prognostic factors for NSCLC patients. CONCLUSIONS SIRT3 is associated with the development and progression of NSCLC. The SIRT3 expression can be used as an independent prognostic factor for NSCLC patients and help identify prognosis of NSCLC. Therefore, SIRT3 has the potential to become a new factor for prognosis prediction and personalized treatment of NSCLC.
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De Matteis S, Granato AM, Napolitano R, Molinari C, Valgiusti M, Santini D, Foschi FG, Ercolani G, Vespasiani Gentilucci U, Faloppi L, Scartozzi M, Frassineti GL, Casadei Gardini A. Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma. Dig Dis Sci 2017; 62:1872-1880. [PMID: 28527050 DOI: 10.1007/s10620-017-4615-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 05/11/2017] [Indexed: 12/16/2022]
Abstract
Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD+)-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.
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Affiliation(s)
- Serena De Matteis
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli, 40, 47014, Meldola, Italy.
| | - Anna Maria Granato
- Immunotherapy and Cell Therapy Unit, IRST IRCCS, Via Maroncelli, 40, 47014, Meldola, Italy
| | - Roberta Napolitano
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli, 40, 47014, Meldola, Italy
| | - Chiara Molinari
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli, 40, 47014, Meldola, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, IRST IRCCS, Via Maroncelli, 40, 47014, Meldola, Italy
| | - Daniele Santini
- Campus Bio-Medico, University of Rome, Via Àlvaro del Portillo, 21, 00128, Rome, Italy
| | | | - Giorgio Ercolani
- Department of General Surgery, Morgagni-Pierantoni Hospital, Via Carlo Forlanini, 34, 47121, Forlì, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti, 9, 40138, Bologna, Italy
| | - Umberto Vespasiani Gentilucci
- Internal Medicine and Hepatology Unit, University Campus Bio-Medico, Via Àlvaro del Portillo, 21, 00128, Rome, Italy
| | - Luca Faloppi
- Medical Oncology, University Hospital, University of Cagliari, SS 554 km 4.500, Monserrato, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University Hospital, University of Cagliari, SS 554 km 4.500, Monserrato, Cagliari, Italy
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SIRT3: Oncogene and Tumor Suppressor in Cancer. Cancers (Basel) 2017; 9:cancers9070090. [PMID: 28704962 PMCID: PMC5532626 DOI: 10.3390/cancers9070090] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/02/2017] [Accepted: 07/07/2017] [Indexed: 12/15/2022] Open
Abstract
Sirtuin 3 (SIRT3), the major deacetylase in mitochondria, plays a crucial role in modulating oxygen reactive species (ROS) and limiting the oxidative damage in cellular components. SIRT3 targets different enzymes which regulate mitochondrial metabolism and participate in ROS detoxification, such as the complexes of the respiratory chain, the isocitrate dehydrogenase, or the manganese superoxide dismutase. Thus, SIRT3 activity is essential in maintaining mitochondria homeostasis and has recently received great attention, as it is considered a fidelity protein for mitochondrial function. In some types of cancer, SIRT3 functions as a tumoral promoter, since it keeps ROS levels under a certain threshold compatible with cell viability and proliferation. On the contrary, other studies describe SIRT3 as a tumoral suppressor, as SIRT3 could trigger cell death under stress conditions. Thus, SIRT3 could have a dual role in cancer. In this regard, modulation of SIRT3 activity could be a new target to develop more personalized therapies against cancer.
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42
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Chen J, Wang A, Chen Q. SirT3 and p53 Deacetylation in Aging and Cancer. J Cell Physiol 2017; 232:2308-2311. [PMID: 27791271 DOI: 10.1002/jcp.25669] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 10/27/2016] [Indexed: 12/23/2022]
Affiliation(s)
- Jijun Chen
- Research and Development; Allonger LLC, Columbia Maryland
- Mei Chen Biotechnology Co. Ltd.; Qingdao, Shan Dong China
| | - Aiqin Wang
- The Affiliated Hospital of Qingdao University; Qingdao, Shan Dong China
| | - Qingqi Chen
- The Affiliated Hospital of Qingdao University; Qingdao, Shan Dong China
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43
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Zeng X, Wang N, Zhai H, Wang R, Wu J, Pu W. SIRT3 functions as a tumor suppressor in hepatocellular carcinoma. Tumour Biol 2017; 39:1010428317691178. [PMID: 28347248 DOI: 10.1177/1010428317691178] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Hepatocellular carcinoma is one of the leading causes for cancer-related mortality worldwide. SIRT3 may function as either oncogene or tumor suppressor in a panel of cancers; however, the role of SIRT3 in hepatocellular carcinoma remains unclear. In this study, we assayed the expression level of SIRT3 in hepatocellular carcinoma tissues by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. A loss-of-function approach was used to examine the effects of SIRT3 on biological activity, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of SIRT3 protein in hepatocellular carcinoma tissues were significantly downregulated compared with those in adjacent non-cancerous tissues. Furthermore, SIRT3 could decrease cell proliferation and inhibit cell migration/invasion in hepatocellular carcinoma cell line. Taken together, these results elucidated the function of SIRT3 in hepatocellular carcinoma development and suggested that SIRT3 might function as tumor suppressor in hepatocellular carcinoma by targeting PI3K/Akt pathway.
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Affiliation(s)
- Xianchun Zeng
- 1 Department of Medical Imaging, Guizhou Provincial People's Hospital, Guiyang, China
| | - Nanzhu Wang
- 1 Department of Medical Imaging, Guizhou Provincial People's Hospital, Guiyang, China
| | - Hui Zhai
- 2 School of Basic Medicine, Guizhou Medical University, Guiyang, China
| | - Rongpin Wang
- 1 Department of Medical Imaging, Guizhou Provincial People's Hospital, Guiyang, China
| | - Jiahong Wu
- 2 School of Basic Medicine, Guizhou Medical University, Guiyang, China
| | - Wei Pu
- 1 Department of Medical Imaging, Guizhou Provincial People's Hospital, Guiyang, China
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Chávez E, Lozano-Rosas MG, Domínguez-López M, Velasco-Loyden G, Rodríguez-Aguilera JR, José-Nuñez C, Tuena de Gómez-Puyou M, Chagoya de Sánchez V. Functional, Metabolic, and Dynamic Mitochondrial Changes in the Rat Cirrhosis-Hepatocellular Carcinoma Model and the Protective Effect of IFC-305. J Pharmacol Exp Ther 2017; 361:292-302. [PMID: 28209723 DOI: 10.1124/jpet.116.239301] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 02/13/2017] [Indexed: 12/25/2022] Open
Abstract
Background: Mitochondrion is an important metabolic and energetic organelle that regulates several cellular processes. Mitochondrial dysfunction has been related to liver diseases including hepatocellular carcinoma. As a result, the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. We previously demonstrated the chemopreventive effect of the hepatoprotector IFC-305. Aim: In this work we aimed to evaluate the functional, metabolic, and dynamic mitochondrial alterations in the sequential model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats and the possible beneficial effect of IFC-305. Methods: Experimental groups of rats were formed to induce cirrhosis-hepatocellular carcinoma and to assess the IFC-305 effect during cancer development and progression through the evaluation of functional, metabolic, and dynamic mitochondrial parameters. Results: In this experimental model, dysfunctional mitochondria were observed and suspension of the diethylnitrosamine treatment was not enough to restore them. Administration of IFC-305 maintained and restored the mitochondrial function and regulated parameters implicated in metabolism as well as the mitochondrial dynamics modified by diethylnitrosamine intoxication. Conclusion: This study supports IFC-305 as a potential hepatocellular carcinoma treatment or as an adjuvant in chemotherapy.
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Affiliation(s)
- Enrique Chávez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
| | - María Guadalupe Lozano-Rosas
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
| | - Mariana Domínguez-López
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
| | - Gabriela Velasco-Loyden
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
| | - Jesús Rafael Rodríguez-Aguilera
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
| | - Concepción José-Nuñez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
| | - Marietta Tuena de Gómez-Puyou
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
| | - Victoria Chagoya de Sánchez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (E.C., M.G.L.-R., M.D.-L., G.V.-L., J.R.R.-A., V.C.S.); and Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (C.J.-N., M.T.G.-P.)
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45
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Xiong Y, Wang M, Zhao J, Wang L, Li X, Zhang Z, Jia L, Han Y. SIRT3 is correlated with the malignancy of non-small cell lung cancer. Int J Oncol 2017; 50:903-910. [PMID: 28197634 DOI: 10.3892/ijo.2017.3868] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 01/30/2017] [Indexed: 11/05/2022] Open
Abstract
The mitochondrial deacetylase SIRT3 plays a pivotal role in the initiation and the progression of certain cancers acting as an oncogene. However, in others it acts anti-oncogenically. Its conflicting action is possibly due to the different key proteins it modifies depending on the context of active intracellular signaling pathways in different cancers. SIRT3 is thus a novel target for preventing and treating cancer. In the present study, we explored the function of SIRT3 in non-small cell lung cancer (NSCLC) with the aim of elucidating the underlying mechanisms. We first determined the SIRT3 expression levels by real-time PCR, western blotting and immunohistochemistry on tissue microarrays of paired samples of NSCLC tissue and adjacent normal tissue from 70 patients with associated clinicopathological data. Levels of SIRT3 protein and mRNA were significantly increased in NSCLC tissue, compared with normal tissue (P<0.05). Expression of SIRT3 in NSCLC positively correlated with that of malignant biomarker Ki-67 (P<0.05) and oncogene p-Akt (P<0.05). Patients with higher SIRT3 expression had a shorter overall survival duration (P<0.05). NSCLC tissue of squamous cell carcinoma type had higher SIRT3 expression compared with other types (P<0.05). Furthermore, among the clinicopathological variables examined, SIRT3 expression was correlated only with pathological type (P<0.05). In NSCLC cell lines, we found that downregulation of SIRT3 by siRNA decreased the activation of Akt, and that SIRT3 overexpression caused the activation of Akt. In addition, in a NSCLC cell line, SIRT3 was able to co-immunoprecipitate Akt and co-located with Akt, suggesting that SIRT3 regulates the activation of Akt through post-transcriptional modification. Our findings suggest that SIRT3 promotes the malignancy of NSCLC, showing an oncogenic preference towards squamous cell carcinoma, and that could represent a novel target for treatment.
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Affiliation(s)
- Yanlu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Mingxing Wang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Lei Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Xiaofei Li
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Zhipei Zhang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yong Han
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
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46
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Zhang H, Shang YP, Chen HY, Li J. Histone deacetylases function as novel potential therapeutic targets for cancer. Hepatol Res 2017; 47:149-159. [PMID: 27457249 DOI: 10.1111/hepr.12757] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 05/29/2016] [Accepted: 05/31/2016] [Indexed: 12/12/2022]
Abstract
Diverse cellular functions, including tumor suppressor gene expression, DNA repair, cell proliferation and apoptosis, are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) are enzymes involved in remodeling of chromatin by deacetylating the lysine residues. They play a pivotal role in epigenetic regulation of gene expression. Dysregulation of HDACs and aberrant chromatin acetylation and deacetylation have been implicated in the pathogenesis of various diseases, including cancer. Histone deacetylases have become a target for the development of drugs for treating cancer because of their major contribution to oncogenic cell transformation. Overexpression of HDACs correlates with tumorigenesis. Previous work showed that inhibition of HDACs results in apoptosis and the inhibition of cell proliferation in multiple cells. A significant number of HDAC inhibitors have been developed in the past decade. These inhibitors have strong anticancer effects in vitro and in vivo, inducing growth arrest, differentiation, and programmed cell death, inhibiting cell migration, invasion, and metastasis, and suppressing angiogenesis. In addition, HDAC-mediated deacetylation alters the transcriptional activity of nuclear transcription factors, including p53, E2F, c-Myc, and nuclear factor-κB, as well as the extracellular signal-regulated kinase1/2, phosphatidylinositol 3-kinase, Notch, and Wnt signaling pathways. This review highlights the role of HDACs in cancer pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.
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Affiliation(s)
- Hui Zhang
- Anhui Provincial Cancer Hospital and West Branch of Anhui Provincial Hospital
| | - Yu-Ping Shang
- Anhui Provincial Cancer Hospital and West Branch of Anhui Provincial Hospital
| | - Hong-Ying Chen
- Anhui Provincial Cancer Hospital and West Branch of Anhui Provincial Hospital
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China
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Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell 2017; 16:4-16. [PMID: 27686535 PMCID: PMC5242307 DOI: 10.1111/acel.12538] [Citation(s) in RCA: 215] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2016] [Indexed: 12/11/2022] Open
Abstract
In mammals, seven members of the sirtuin protein family known as class III histone deacetylase have been identified for their characteristic features. These distinguished characteristics include the tissues where they are distributed or located, enzymatic activities, molecular functions, and involvement in diseases. Among the sirtuin members, SIRT3 has received much attention for its role in cancer genetics, aging, neurodegenerative disease, and stress resistance. SIRT3 controls energy demand during stress conditions such as fasting and exercise as well as metabolism through the deacetylation and acetylation of mitochondrial enzymes. SIRT3 is well known for its ability to eliminate reactive oxygen species and to prevent the development of cancerous cells or apoptosis. This review article provides a comprehensive review on numerous (noteworthy) molecular functions of SIRT3 and its effect on cancer cells and various diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.
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Affiliation(s)
- Aneesa Ansari
- Department of Genetic Engineering and Biotechnology; Jessore University of Science and Technology; Jessore 7408 Bangladesh
| | - Md. Shahedur Rahman
- Department of Genetic Engineering and Biotechnology; Jessore University of Science and Technology; Jessore 7408 Bangladesh
| | - Subbroto K. Saha
- Department of Stem Cell and Regenerative Biology; Konkuk University; 120 Neungdong-Ro Seoul 05029 Korea
| | - Forhad K. Saikot
- Department of Genetic Engineering and Biotechnology; Jessore University of Science and Technology; Jessore 7408 Bangladesh
| | - Akash Deep
- Central Scientific Instruments Organisation (CSIR-CSIO); Sector 30 C Chandigarh 160030 India
| | - Ki-Hyun Kim
- Department of Civil & Environmental Engineering; Hanyang University; 222 Wangsimni-Ro Seoul 04763 Korea
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Park SH, Phuc NM, Lee J, Wu Z, Kim J, Kim H, Kim ND, Lee T, Song KS, Liu KH. Identification of acetylshikonin as the novel CYP2J2 inhibitor with anti-cancer activity in HepG2 cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2017; 24:134-140. [PMID: 28160853 DOI: 10.1016/j.phymed.2016.12.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 11/28/2016] [Accepted: 12/01/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND Acetylshikonin is one of the biologically active compounds derived from the root of Lithospermum erythrorhizon, a medicinal plant with anti-cancer and anti-inflammation activity. Although there have been a few previous reports demonstrating that acetylshikonin exerts anti-cancer activity in vitro and in vivo, it is still not clear what is the exact molecular target protein of acetylshikonin in cancer cells. PURPOSE The purpose of this study is to evaluate the inhibitory effect of acetylshikonin against CYP2J2 enzyme which is predominantly expressed in human tumor tissues and carcinoma cell lines. STUDY DESIGN The inhibitory effect of acetylshikonin on the activities of CYP2J2-mediated metabolism were investigated using human liver microsomes (HLMs), and its cytotoxicity against human hepatoma HepG2 cells was also evaluated. METHOD Astemizole, a representative CYP2J2 probe substrate, was incubated in HLMs in the presence or absence of acetylshikonin. After incubation, the samples were analyzed by liquid chromatography and triple quadrupole mass spectrometry. The anti-cancer activity of acetylshikonin was evaluated on human hepatocellular carcinoma HepG2 cells. WST-1, cell counting, and colony formation assays were further adopted for the estimation of the growth rate of HepG2 cells treated with acetylshikonin. RESULTS Acetylshikonin inhibited CYP2J2-mediated astemizole O-demethylation activity (Ki = 2.1µM) in a noncompetitive manner. The noncompetitive inhibitory effect of acetylshikonin on CYP2J2 enzyme was also demonstrated using this 3D structure, which showed different binding location of astemizole and acetylshikonin in CYP2J2 model. It showed cytotoxic effects against human hepatoma HepG2 cells (IC50 = 2μM). In addition, acetylshikonin treatment inhibited growth of human hepatocellular carcinoma HepG2 cells leading to apoptosis accompanied with p53, bax, and caspase3 activation as well as bcl2 down-regulation. CONCLUSION Taken together, our present study elucidates acetylshikonin displays the inhibitory effects against CYP2J2 in HLMs and anti-cancer activity in human hepatocellular carcinoma HepG2 cells.
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Affiliation(s)
- See-Hyoung Park
- Department of Bio and Chemical Engineering, Hongik University, Sejong 30016, Republic of Korea
| | - Nguyen Minh Phuc
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jongsung Lee
- Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Zhexue Wu
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jieun Kim
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Hyunkyoung Kim
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Nam Doo Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Taeho Lee
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Kyung-Sik Song
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
| | - Kwang-Hyeon Liu
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
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Xiong Y, Wang M, Zhao J, Han Y, Jia L. Sirtuin 3: A Janus face in cancer (Review). Int J Oncol 2016; 49:2227-2235. [DOI: 10.3892/ijo.2016.3767] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 11/03/2016] [Indexed: 11/06/2022] Open
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50
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Osborne B, Bentley NL, Montgomery MK, Turner N. The role of mitochondrial sirtuins in health and disease. Free Radic Biol Med 2016; 100:164-174. [PMID: 27164052 DOI: 10.1016/j.freeradbiomed.2016.04.197] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 04/21/2016] [Accepted: 04/29/2016] [Indexed: 01/15/2023]
Abstract
Mitochondria play a critical role in energy production, cell signalling and cell survival. Defects in mitochondrial function contribute to the ageing process and ageing-related disorders such as metabolic disease, cancer, and neurodegeneration. The sirtuin family of deacylase enzymes have a variety of subcellular localisations and have been found to remove a growing list of post-translational acyl modifications from target proteins. SIRT3, SIRT4, and SIRT5 are found primarily located in the mitochondria, and are involved in many of the key processes of this organelle. SIRT3 has been the subject of intense research and is primarily a deacetylase thought to function as a mitochondrial fidelity protein, with roles in mitochondrial substrate metabolism, protection against oxidative stress, and cell survival pathways. Less is known about the functional targets of SIRT4, which has deacetylase, ADP-ribosylase, and a newly-described lipoamidase function, although key roles in lipid and glutamine metabolism have been reported. SIRT5 modulates a host of newly-discovered acyl modifications including succinylation, malonylation, and glutarylation in both mitochondrial and extra-mitochondrial compartments, however the functional significance of SIRT5 in the regulation of many of its proposed target proteins remains to be discovered. Because of their influence on a broad range of pathways, SIRT3, SIRT4, and SIRT5 are implicated in a range of disease-states including metabolic disease such as diabetes, neurodegenerative diseases, cancer, and ageing-related disorders such as hearing-loss and cardiac dysfunction. We review the current knowledge on the function of the three mitochondrial sirtuins, their role in disease, and the current outstanding questions in the field.
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Affiliation(s)
- Brenna Osborne
- Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Nicholas L Bentley
- Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Magdalene K Montgomery
- Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Nigel Turner
- Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
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