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Haddadi G, Lam B, Akhtar S, Yavelberg L, Jamnik V, Roudier E. The MDM2 SNP309 differentially impacts cardiorespiratory fitness in young healthy women and men. Eur J Appl Physiol 2025; 125:1371-1383. [PMID: 39681743 DOI: 10.1007/s00421-024-05682-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024]
Abstract
PURPOSE Maximal oxygen consumption (VO2max), the predominant index of cardiorespiratory fitness (CRF), is a predictor of whole-body function and longevity in humans. The central cardiac function and the skeletal muscle's capacity to use oxygen are key determinants of VO2max. Murine Double Minute 2 (MDM2), mainly known as an oncogene, could regulate myocardial hypertrophy, skeletal muscle angiogenesis, and oxidative phosphorylation. A prevalent single nucleotide polymorphism in the MDM2 promoter (SNP309) substitutes a T for a G, supporting a greater transcriptional activity. We aim to assess whether SNP309 impacts intrinsic CRF. METHODS 82 young healthy nonathletic male and female adults aged 23 ± 2 years performed cardiorespiratory exercise testing to determine their VO2max (mL kg-1 min-1). The genomic DNAs isolated from saliva were genotyped using Taqman-based qPCR. RESULTS A one-way ANOVA showed that SNP309 influenced relative VO2max in the whole cohort (p = 0.044) and in men (p = 0.009), remaining non-significant in women (p = 0.133). VO2max was higher in TT homozygotes than in GT heterozygotes (whole cohort, 47 ± 12 vs. 42 ± 6 mL kg-1 min-1, p = 0.030; men, 53 ± 8 vs. 45 ± 6 mL kg-1 min-1, p = 0.011). A contingency analysis revealed a positive association between SNP309 in men in which the TT genotype was more frequent in the high VO2max group (p = 0.006). When considering G as the dominant allele, men bearing a G allele had lower relative VO2max than TT homozygotes (47 ± 7 vs. 53 ± 8, GG/GT vs. TT, p = 0.010). Conversely, women bearing a G allele had a higher relative VO2max than TT homozygotes (39 ± 5 vs. 34 ± 7, GG/GT vs. TT, p = 0.047). CONCLUSION SNP309 impacts VO2max in a sex-dependent manner in our cohort.
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Affiliation(s)
- Ghazal Haddadi
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Brian Lam
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Sokaina Akhtar
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Loren Yavelberg
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Veronica Jamnik
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Emilie Roudier
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
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Li S, Huang K, Xu C, Zhang H, Wang X, Zhang R, Lu Y, Mohan M, Hu C. DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis. Nucleic Acids Res 2025; 53:gkaf319. [PMID: 40287828 PMCID: PMC12034038 DOI: 10.1093/nar/gkaf319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 03/31/2025] [Accepted: 04/25/2025] [Indexed: 04/29/2025] Open
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), a member of the CMGC group of kinases, is linked to metabolic syndrome, though the underlying molecular mechanisms remain unclear. In this study, we show that Dyrk1b expression is induced in the liver by fasting and in diabetic mice. Through both in vivo and in vitro experiments, we demonstrate that DYRK1B promotes hepatic gluconeogenesis and glucose intolerance. Liver-specific Dyrk1b conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacts with and phosphorylates FOXO1, primarily at Thr467/Ser468, which is essential for its nuclear localization. Additionally, DYRK1B inhibits AKT-mediated FOXO1 phosphorylation at Thr24 and Ser256, enhancing its nuclear retention. DYRK1B-mediated phosphorylation increases the expression of gluconeogenic genes and promotes gluconeogenesis. Further, AZ191, a pharmacological inhibitor of DYRK1B, significantly reduced blood glucose levels in diabetic mice. Collectively, these findings provide new insights into the role of DYRK1B in glucose metabolism and identify it as a new therapeutic target for treating diabetes.
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Affiliation(s)
- Shanshan Li
- Shanghai Diabetes Institute, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Kai Huang
- Department of Sports Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Chu Xu
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hong Zhang
- Shanghai Diabetes Institute, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Xiao Wang
- Key Laboratory of Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310002, Zhejiang, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yan Lu
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Man Mohan
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
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Zheng Q, Lin R, Li Z, Zheng Q, Xu W. Taurine is a potential therapy for rheumatoid arthritis via targeting FOXO3 through cellular senescence and autophagy. PLoS One 2025; 20:e0318311. [PMID: 40238799 PMCID: PMC12002484 DOI: 10.1371/journal.pone.0318311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 01/13/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease closely related to aging with unclear pathogenic mechanisms. This study aims to identify the biomarkers in RA, aging and autophagy using bioinformatics and machine learning and explore the binding stability of taurine to target utilizing computer-aided drug design (CADD). METHODS We identified differentially expressed genes (DEGs) for RA, then crossed with gene libraries for aging and autophagy to identify common genes (Co-genes). We performed Gene Ontology (GO), Kyoto Encyclopedia of the Genome (KEGG), and ClueGO analysis for Co-genes. The Co-genes were subjected to support vector machine-recursive feature elimination (SVM-RFE), Degree, and Betweenness algorithms to get hub genes, then verified by an artificial neural network (ANN). After continuing to perform least absolute shrinkage and selection operator (LASSO) and weighted gene co-expression network analysis (WGCNA) on Co-genes, the results were crossed with hub genes to obtain genes, which were imported into various validation sets for receiver operating characteristics (ROC) to identify key genes. We analyzed the microRNA/TF network, enriched pathways, and immune cell infiltration for key genes. The binding stability of taurine with the target protein was verified by CADD. Finally, we used Western blot for in vitro experimental verification. RESULTS We obtained 74 Co-genes enriched in RA, cellular senescence, and regulation of programmed cell death. The model prediction of hub genes works well in ANN. The key genes (MMP9, CXCL10, IL15, FOXO3) were tested in ROC with excellent efficacy. In RA, FOXO3 expression was down-regulated while MMP9, CXCL10, and IL15 expression were upregulated, and FOXO3 was negatively correlated with MMP9, CXCL10, and IL15. Two miRNAs (hsa-mir-21-5p, hsa-mir-129-2-3p) and four TFs (CTCF, KLF, FOXC1, TP53) were associated with key genes. The immune cells positively correlated with MMP9, CXCL10, and IL15 expression and negatively correlated with FOXO3 expression were Plasma cells, CD8 T cells, memory-activated CD4 T cells, and follicular helper T cells, aggregating in RA. The binding stability of taurine with FOXO3 was verified by molecular docking and molecular dynamics simulation. In vitro experiments have indicated that taurine can upregulate the expression of FOXO3 and treat RA through the FOXO3-Parkin signaling pathway. CONCLUSIONS MMP9, CXCL10, IL15, and FOXO3 are biomarkers of RA, cellular senescence, and autophagy. Taurine might be a promising drug against RA via targeting cellular senescence and autophagy through FOXO3.
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Affiliation(s)
- Qingcong Zheng
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Rongjie Lin
- Department of Orthopedic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Zhechen Li
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qingzhu Zheng
- Department of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, China
| | - Weihong Xu
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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Fefilova E, Kirdeeva Y, Parfenyev S, Daks A, Fedorova O, Sorokina M, Ha NX, Huong TT, Loc VT, Hai PT, Cuong NM, Barlev N, Shuvalov O. MDM2 up-regulates the energy metabolism in NSCLC in a p53-independent manner. Biochem Biophys Res Commun 2025; 743:151169. [PMID: 39693937 DOI: 10.1016/j.bbrc.2024.151169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 12/20/2024]
Abstract
Although an E3 ligase MDM2 is the major negative regulator of the p53 tumor suppressor, a growing body of evidence suggests its p53-independent oncogenic properties. In particular, MDM2 has been shown to regulate serine metabolism independently of p53 status in several types of neoplasia, including NSCLC. Using the GSEA approach and publicly available molecular data on NSCLC tumors, our bioinformatics data suggest that MDM2 affects a number of metabolic genes, particularly those encoding components of the electron transport chain (ETC). To experimentally elucidate the role of MDM2 in respiration and energy metabolism of NSCLC cell models, we established NSCLC cell lines (WT p53+ A549 and p53-null H1299) overexpressing wild-type MDM2, or its catalytically deficient (C464A) mutant (MUT), or the control vector. Using TMRE staining and SeaHorse energy profiling, we demonstrated that wild-type MDM2, but not its catalytically inactive mutant, significantly increased mitochondrial membrane potential (MMP), glycolysis, respiration, and ATP production in a p53-independent manner. Further, we compared MDM2-associated effects of two natural compounds that, according to our docking experiment data, bind MDM2 with affinities similar to nutlin-3A, ganoderic acid A and berberine. Despite the fact that both nutlin-3A and berberine stabilized the MDM2 protein, they displayed differential effects on energy metabolism. Taken together, our data argue that MDM2 affects energy metabolism likely in a p53-independent manner. These results also highlight another pharmacological dimension of using MDM2-targeting compounds as potent inhibitors of glycolysis and respiration in tumor cells.
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Affiliation(s)
- Elizaveta Fefilova
- Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia
| | - Yulia Kirdeeva
- Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia
| | - Sergey Parfenyev
- Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia
| | - Alexandra Daks
- Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia
| | - Olga Fedorova
- Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia
| | - Margarita Sorokina
- Almazov National Medical Research Centre, 197341, St. Petersburg, Russia
| | - Nguyen Xuan Ha
- Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), 122100, Hanoi, Viet Nam
| | - Tran Thu Huong
- Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), 122100, Hanoi, Viet Nam
| | - Vu Thanh Loc
- Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), 122100, Hanoi, Viet Nam
| | - Pham The Hai
- University of Sciences and Technology of Hanoi (VAST), 122100, Hanoi, Viet Nam
| | - Nguyen Manh Cuong
- Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), 122100, Hanoi, Viet Nam.
| | - Nickolai Barlev
- Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia; Department of Biomedical Studies, Nazarbayev University School of Medicine, Astana, 001000, Kazakhstan.
| | - Oleg Shuvalov
- Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia.
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Wang Z, Sun S, Huang L, Chen X, Xu H, Ma H, Xiao M, Wang L. METTL3/YTHDF1-mediated m 6A modification stabilizes USP12 to deubiquitinate FOXO3 and promote apoptosis in sepsis-induced myocardial dysfunction. Mol Immunol 2025; 177:17-31. [PMID: 39662205 DOI: 10.1016/j.molimm.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/18/2024] [Accepted: 12/01/2024] [Indexed: 12/13/2024]
Abstract
Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication primarily driven by inflammation, yet its molecular mechanisms remain unclear. In this study, we identified significant upregulation of the m6A methyltransferase METTL3 (methyltransferase-like 3), the m6A reader protein YTHDF1 (YTH N6-methyladenosine RNA binding protein 1), as well as increased expression levels of USP12 (ubiquitin-specific peptidase 12), FOXO3 (forkhead box O3), and key molecules in the intrinsic apoptotic pathway, PUMA (p53 upregulated modulator of apoptosis) and BAX (Bcl-2-associated X), through proteomic profiling in an LPS (Lipopolysaccharide)-induced SIMD mouse model. In vitro and in vivo experiments demonstrated that METTL3 and YTHDF1 regulated USP12 mRNA expression and stability through m6A modification. Elevated USP12 interacted with FOXO3, preventing its ubiquitin-mediated degradation, which enhanced FOXO3 binding to the PUMA promoter, leading to upregulation of PUMA. PUMA upregulation initiated the intrinsic apoptotic pathway, activating downstream BAX, Apaf1 (apoptotic protease-activating factor 1), and Caspases, ultimately driving SIMD. Inhibition of METTL3 (with STM2457), YTHDF1 (with Ebselen), or PUMA (with CLZ-8) significantly suppressed intrinsic apoptosis and alleviated SIMD symptoms. These findings underscore the critical role of METTL3/YTHDF1-dependent m6A modification in modulating the USP12-FOXO3-PUMA-BAX-Apaf1-Caspases signaling axis in SIMD, and suggest that targeting this pathway may offer a potential therapeutic strategy for SIMD.
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Affiliation(s)
- Zhiping Wang
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, China, Medical school of Nantong University, Nantong 226001, China; Nantong Fourth People's Hospital, Nantong 226005, China
| | - Simiao Sun
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, China, Medical school of Nantong University, Nantong 226001, China
| | - Lili Huang
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, China, Medical school of Nantong University, Nantong 226001, China
| | - Xinlong Chen
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, China, Medical school of Nantong University, Nantong 226001, China
| | - Huifen Xu
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, China, Medical school of Nantong University, Nantong 226001, China
| | - Hongwei Ma
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, China, Medical school of Nantong University, Nantong 226001, China
| | - Mingbing Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China; Department of Laboratory Medicine, Affiliated Hospital and Medical School of Nantong University, Nantong, Jiangsu, China.
| | - Linhua Wang
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, China, Medical school of Nantong University, Nantong 226001, China.
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Guo J, Wang J, Zhang P, Wen P, Zhang S, Dong X, Dong J. TRIM6 promotes glioma malignant progression by enhancing FOXO3A ubiquitination and degradation. Transl Oncol 2024; 46:101999. [PMID: 38759605 PMCID: PMC11127279 DOI: 10.1016/j.tranon.2024.101999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/23/2024] [Accepted: 05/14/2024] [Indexed: 05/19/2024] Open
Abstract
PURPOSE TRIM6, an E3 ubiquitin ligase with tripartite motif, directly targets protein substrates for degradation through ubiquitination. Studies have shown that TRIM6 plays a significant role in tumor development in various human malignancies. Thus, the aim of this study was to investigate the importance of TRIM6 and its associated mechanism in promoting the progression of glioma. METHODS The expression of TRIM6 and its prognostic value in glioma patients were collected from the TCGA and CGGA databases. The effects of TRIM6 on glioma were investigated in vitro by CCK8, colony formation, wound healing, and transwell assays. Co-IP and western blot analysis were used to detect the interaction between TRIM6 and FOXO3A. The effects of TRIM6 were verified in vivo in subcutaneously xenograft models, and tumor size, and immunohistochemical changes were observed. RESULTS Our analysis of TRIM6 expression in glioma tissues revealed a high level of expression, and the heightened expression of TRIM6 showed a positive correlation with the unfavorable prognosis among glioma/GBM patients. Through loss-of-function and gain-of-function experiments, we observed a profound impact on the proliferation, invasion, and migration abilities of glioma cells both in vitro and in vivo upon deletion of TRIM6. Conversely, the overexpression of TRIM6 intensified the malignant characteristics of glioma. Additionally, our findings revealed a significant interaction between TRIM6 and FOXO3A, wherein TRIM6 contributed to the destabilization of FOXO3A protein by promoting its ubiquitination and subsequent degradation. Experiments conducted in the rescue study affirmed that the promotion of glioma cell proliferation, invasion, and migration is facilitated by TRIM6 through the suppression of FOXO3A protein levels. CONCLUSIONS These observations imply that the TRIM6-FOXO3A axis could potentially serve as an innovative focus for intervening in glioma.
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Affiliation(s)
- Jingpeng Guo
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; Department of Neurosurgery, Fuyang People's Hospital, Fuyang, Anhui 236000, China
| | - Ji Wang
- Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, China
| | - Peng Zhang
- Department of Neurosurgery, The People's Hospital of Rugao, Nantong, Jiangsu 226500, China
| | - Ping Wen
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Shoudan Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Xuchen Dong
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Jun Dong
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
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Sha X, Zou X, Liu S, Guan C, Shi W, Gao J, Zhong X, Jiang X. Forkhead box O1 in metabolic dysfunction-associated fatty liver disease: molecular mechanisms and drug research. Front Nutr 2024; 11:1426780. [PMID: 39021599 PMCID: PMC11253077 DOI: 10.3389/fnut.2024.1426780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 06/21/2024] [Indexed: 07/20/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease that progresses from hepatic steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer, posing a huge burden on human health. Existing research has confirmed that forkhead box O1 (FOXO1), as a member of the FOXO transcription factor family, is upregulated in MAFLD. Its activity is closely related to nuclear-cytoplasmic shuttling and various post-translational modifications including phosphorylation, acetylation, and methylation. FOXO1 mediates the progression of MAFLD by regulating glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, hepatic fibrosis, hepatocyte autophagy, apoptosis, and immune inflammation. This article elaborates on the regulatory role of FOXO1 in MAFLD, providing a summary and new insights for the current status of drug research and targeted therapies for MAFLD.
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Affiliation(s)
| | | | | | | | | | | | - Xiangyu Zhong
- General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xingming Jiang
- General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
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Tosios KI, Kalogirou EM, Koutlas IG. Association of MDM2 Overexpression in Ameloblastomas with MDM2 Amplification and BRAF V600E Expression. Int J Mol Sci 2024; 25:2238. [PMID: 38396916 PMCID: PMC10889355 DOI: 10.3390/ijms25042238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/01/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
Ameloblastoma is a rare tumor but represents the most common odontogenic neoplasm. It is localized in the jaws and, although it is a benign, slow-growing tumor, it has an aggressive local behavior and high recurrence rate. Therefore, alternative treatment options or complementary to surgery have been evaluated, with the most promising one among them being a targeted therapy with the v-Raf murine sarcoma viral oncogene homologue B (BRAF), as in ameloblastoma the activating mutation V600E in BRAF is common. Studies in other tumors have shown that the synchronous inhibition of BRAF and human murine double minute 2 homologue (MDM2 or HDM2) protein is more effective than BRAF monotherapy, particularly in the presence of wild type p53 (WTp53). To investigate the MDM2 protein expression and gene amplification in ameloblastoma, in association with BRAFV600E and p53 expression. Forty-four cases of ameloblastoma fixed in 10% buffered formalin and embedded in paraffin were examined for MDM2 overexpression and BRAFV600E and p53 expression by immunohistochemistry, and for MDM2 ploidy with fluorescence in situ hybridization. Sixteen of forty-four (36.36%) cases of ameloblastoma showed MDM2 overexpression. Seven of sixteen MDM2-positive ameloblastomas (43.75%) were BRAFV600E positive and fifteen of sixteen MDM2-positive ameloblastomas (93.75%) were p53 negative. All MDM2 overexpressing tumors did not show copy number alterations for MDM2. Overexpression of MDM2 in ameloblastomas is not associated with MDM2 amplification, but most probably with MAPK activation and WTp53 expression. Further verification of those findings could form the basis for the use of MDM2 expression as a marker of MAPK activation in ameloblastomas and the trial of dual BRAF/MDM2 inhibition in the management of MDM2-overexpressing/BRAFV600E-positive/WTp53 ameloblastomas.
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Affiliation(s)
- Konstantinos I. Tosios
- Department of Oral Pathology & Medicine and Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Marina Kalogirou
- Faculty of Health and Rehabilitation Sciences, Metropolitan College, 15125 Athens, Greece;
| | - Ioannis G. Koutlas
- Division of Oral Pathology, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA;
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Tang Z, Zhang Y, Yu Z, Luo Z. Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a. Int J Mol Sci 2023; 24:16611. [PMID: 38068934 PMCID: PMC10705988 DOI: 10.3390/ijms242316611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 12/18/2023] Open
Abstract
Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.
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Affiliation(s)
- Zhimin Tang
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
| | - Yilan Zhang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhengyi Yu
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhijun Luo
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
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Yabushita T, Chinen T, Nishiyama A, Asada S, Shimura R, Isobe T, Yamamoto K, Sato N, Enomoto Y, Tanaka Y, Fukuyama T, Satoh H, Kato K, Saitoh K, Ishikawa T, Soga T, Nannya Y, Fukagawa T, Nakanishi M, Kitagawa D, Kitamura T, Goyama S. Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment. Cell Rep 2023; 42:113098. [PMID: 37714156 DOI: 10.1016/j.celrep.2023.113098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 06/22/2023] [Accepted: 08/21/2023] [Indexed: 09/17/2023] Open
Abstract
Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.
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Affiliation(s)
- Tomohiro Yabushita
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takumi Chinen
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Atsuya Nishiyama
- Division of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shuhei Asada
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan
| | - Ruka Shimura
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Tomoya Isobe
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keita Yamamoto
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Naru Sato
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yutaka Enomoto
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yosuke Tanaka
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomofusa Fukuyama
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Hematology, International University of Health and Welfare Hospital, Tochigi, Japan
| | - Hitoshi Satoh
- Division of Medical Genome Sciences, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Keiko Kato
- Infinity Lab, INC, Yamagata, Japan; Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Kaori Saitoh
- Infinity Lab, INC, Yamagata, Japan; Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Takamasa Ishikawa
- Infinity Lab, INC, Yamagata, Japan; Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Yasuhito Nannya
- Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tatsuo Fukagawa
- Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Makoto Nakanishi
- Division of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Daiju Kitagawa
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Toshio Kitamura
- Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
| | - Susumu Goyama
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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11
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RAB3D/MDM2/β-catenin/c-MYC axis exacerbates the malignant behaviors of acute myeloid leukemia cells in vitro and in vivo. Cancer Gene Ther 2023; 30:335-344. [PMID: 36280757 DOI: 10.1038/s41417-022-00549-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 09/30/2022] [Accepted: 10/06/2022] [Indexed: 11/08/2022]
Abstract
RAB3D, a small Ras-like GTPase involved in regulating secretory pathway, plays a cancer-promoting role in several solid tumors. However, its role in leukemogenesis remains unknown yet. Acute myeloid leukemia (AML) is a common acute leukemia with a high mortality. Here, we found the higher expression of RAB3D in bone marrow mononuclear cells derived from AML patients (n = 54) versus healthy participants (n = 20). The following loss- and gain-of-function experiments demonstrated that RAB3D promoted growth, enhanced colony formation and accelerated G1/S transition of U937, THP-1 and KG-1 AML cells. RAB3D silencing inhibited tumorigenesis of AML cells in vivo and delayed AML cells-induced death of mice. Interestingly, the expression of RAB3D is positively correlated with that of an oncogene mouse double minute 2 (MDM2) in bone marrow mononuclear cells of AML patients (r = 0.923, p < 0.001). Intracellular MDM2 was conjugated with more ubiquitins and degraded faster when RAB3D was silenced. A commonly therapeutic target of AML, β-catenin signaling, was activated by RAB3D overexpression, but deactivated after MDM2 was silenced. The RAB3D-induced proliferation acceleration and β-catenin activation were abolished by MDM2 knockdown, implying that RAB3D function by stabilizing MDM2. In addition, c-MYC, a β-catenin downstream effector, was recruited directly to the RAB3D gene promoter (-360/-349 and -136/-125 sites) and induced its transcription. Collectively, this study demonstrates that RAB3D may exacerbate the malignant behaviors of AML cells through forming a positive feedback loop with MDM2/β-catenin/c-MYC signaling. RAB3D might be a novel target of clinical AML treatment.
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12
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Bernardo VS, Torres FF, da Silva DGH. FoxO3 and oxidative stress: a multifaceted role in cellular adaptation. J Mol Med (Berl) 2023; 101:83-99. [PMID: 36598531 DOI: 10.1007/s00109-022-02281-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 01/05/2023]
Abstract
Oxidative stress is a major cause of morbidity and mortality in human health and disease. In this review, we focus on the Forkhead Box (Fox) subclass O3 (FoxO3), an extensively studied transcription factor that plays a pleiotropic role in a wide range of physiological and pathological processes by regulating multiple gene regulatory networks involved in the modulation of numerous aspects of cellular metabolism, including fuel metabolism, cell death, and stress resistance. This review will also focus on regulatory mechanisms of FoxO3 expression and activity, such as crucial post-translational modifications and non-coding RNAs. Moreover, this work discusses and evidences some pathways to how this transcription factor and reactive oxygen species regulate each other, which may lead to the pathogenesis of various types of diseases. Therefore, in addition to being a promising therapeutic target, the FoxO3-regulated signaling pathways can also be used as reliable diagnostic and prognostic biomarkers and indicators for drug responsiveness.
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Affiliation(s)
| | | | - Danilo Grünig Humberto da Silva
- Department of Biology, Universidade Estadual Paulista (UNESP), São Paulo, Brazil.
- Campus de Três Lagoas, Universidade Federal de Mato Grosso Do Sul (CPTL/UFMS), Avenida Ranulpho Marques Leal, 3484, Três Lagoas, Mato Grosso Do Sul, Distrito Industrial-Post code 79613-000, Brazil.
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13
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Role of FOXO3a Transcription Factor in the Regulation of Liver Oxidative Injury. Antioxidants (Basel) 2022; 11:antiox11122478. [PMID: 36552685 PMCID: PMC9774119 DOI: 10.3390/antiox11122478] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Oxidative stress has been identified as a key mechanism in liver damage caused by various chemicals. The transcription factor FOXO3a has emerged as a critical regulator of redox imbalance. Multiple post-translational changes and epigenetic processes closely regulate the activity of FOXO3a, resulting in synergistic or competing impacts on its subcellular localization, stability, protein-protein interactions, DNA binding affinity, and transcriptional programs. Depending on the chemical nature and subcellular context, the oxidative-stress-mediated activation of FOXO3a can induce multiple transcriptional programs that play crucial roles in oxidative injury to the liver by chemicals. Here, we mainly review the role of FOXO3a in coordinating programs of genes that are essential for cellular homeostasis, with an emphasis on exploring the regulatory mechanisms and potential application of FOXO3a as a therapeutic target to prevent and treat liver oxidative injury.
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14
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Gui T, Burgering BMT. FOXOs: masters of the equilibrium. FEBS J 2022; 289:7918-7939. [PMID: 34610198 PMCID: PMC10078705 DOI: 10.1111/febs.16221] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/22/2021] [Accepted: 10/04/2021] [Indexed: 01/14/2023]
Abstract
Forkhead box O (FOXO) transcription factors (TFs) are a subclass of the larger family of forkhead TFs. Mammalians express four members FOXO1, FOXO3, FOXO4, and FOXO6. The interest in FOXO function stems mostly from their observed role in determining lifespan, where in model organisms, increased FOXO activity results in extended lifespan. FOXOs act as downstream of several signaling pathway and are extensively regulated through post-translational modifications. The transcriptional program activated by FOXOs in various cell types, organisms, and under various conditions has been described and has shed some light on what the critical transcriptional targets are in mediating FOXO function. At the cellular level, these studies have revealed a role for FOXOs in cell metabolism, cellular redox, cell proliferation, DNA repair, autophagy, and many more. The general picture that emerges hereof is that FOXOs act to preserve equilibrium, and they are important for cellular homeostasis. Here, we will first briefly summarize the general knowledge of FOXO regulation and possible functions. We will use genomic stability to illustrate how FOXOs ensure homeostasis. Genomic stability is critical for maintaining genetic integrity, and therefore preventing disease. However, genomic mutations need to occur during lifetime to enable evolution, yet their accumulation is believed to be causative to aging. Therefore, the role of FOXO in genomic stability may underlie its role in lifespan and aging. Finally, we will come up with questions on some of the unknowns in FOXO function, the answer(s) to which we believe will further our understanding of FOXO function and ultimately may help to understand lifespan and its consequences.
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Affiliation(s)
- Tianshu Gui
- Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht and the Oncode Institute, The Netherlands
| | - Boudewijn M T Burgering
- Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht and the Oncode Institute, The Netherlands
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15
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Chen L, Zhu L, Fang J, Zhang N, Li D, Sheng X, Zhou J, Wang S, Wang J. Circular RNA circFoxo3 Promotes Granulosa Cell Apoptosis Under Oxidative Stress Through Regulation of FOXO3 Protein. DNA Cell Biol 2022; 41:1026-1037. [DOI: 10.1089/dna.2022.0449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Linjun Chen
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Lihua Zhu
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Junshun Fang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Ningyuan Zhang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Dong Li
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Xiaoqiang Sheng
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Jidong Zhou
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Shanshan Wang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
| | - Jie Wang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China
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16
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Vitto VAM, Bianchin S, Zolondick AA, Pellielo G, Rimessi A, Chianese D, Yang H, Carbone M, Pinton P, Giorgi C, Patergnani S. Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy. Biomedicines 2022; 10:1596. [PMID: 35884904 PMCID: PMC9313210 DOI: 10.3390/biomedicines10071596] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/25/2022] [Accepted: 06/30/2022] [Indexed: 01/18/2023] Open
Abstract
Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.
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Affiliation(s)
- Veronica Angela Maria Vitto
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Silvia Bianchin
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alicia Ann Zolondick
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
- Department of Molecular Biosciences and Bioengineering, University of Hawai’i at Manoa, Honolulu, HI 96816, USA
| | - Giulia Pellielo
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alessandro Rimessi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Diego Chianese
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Haining Yang
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Paolo Pinton
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Simone Patergnani
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
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17
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The FOXO family of transcription factors: key molecular players in gastric cancer. J Mol Med (Berl) 2022; 100:997-1015. [PMID: 35680690 DOI: 10.1007/s00109-022-02219-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/19/2022] [Accepted: 06/01/2022] [Indexed: 10/18/2022]
Abstract
Gastric cancer (GC) is the fifth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related death with an oncological origin. Despite its decline in incidence and mortality in recent years, GC remains a global public problem that seriously threatens patients' health and lives. The forkhead box O proteins (FOXOs) are a family of evolutionarily conserved transcription factors (TFs) with crucial roles in cell fate decisions. In mammals, the FOXO family consists of four members FOXO1, 3a, 4, and 6. FOXOs play crucial roles in a variety of biological processes, such as development, metabolism, and stem cell maintenance, by regulating the expression of their target genes in space and time. An accumulating amount of evidence has shown that the dysregulation of FOXOs is involved in GC progression by affecting multiple cellular processes, including proliferation, apoptosis, invasion, metastasis, cell cycle progression, carcinogenesis, and resistance to chemotherapeutic drugs. In this review, we systematically summarize the recent findings on the regulatory mechanisms of FOXO family expression and activity and elucidate its roles in GC progression. Moreover, we also highlight the clinical implications of FOXOs in GC treatment.
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18
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Chen M, Choi S, Wen T, Chen C, Thapa N, Lee JH, Cryns VL, Anderson RA. A p53-phosphoinositide signalosome regulates nuclear AKT activation. Nat Cell Biol 2022; 24:1099-1113. [PMID: 35798843 PMCID: PMC9833102 DOI: 10.1038/s41556-022-00949-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 05/26/2022] [Indexed: 01/13/2023]
Abstract
The tumour suppressor p53 and PI3K-AKT pathways have fundamental roles in the regulation of cell growth and apoptosis, and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear AKT activation through a p53-dependent mechanism that is distinct from the canonical membrane-localized PI3K-AKT pathway. Following genotoxic stress, a nuclear PI3K binds p53 in the non-membranous nucleoplasm to generate a complex of p53 and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), which recruits AKT, PDK1 and mTORC2 to activate AKT and phosphorylate FOXO proteins, thereby inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear AKT in an on/off fashion following stress, whereas mutant p53 dose-dependently stimulates high basal AKT activity. The p53-PtdIns(3,4,5)P3 complex is dephosphorylated to p53-phosphatidylinositol 4,5-bisphosphate by PTEN to inhibit AKT activation. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, which underscores its therapeutic relevance.
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Affiliation(s)
- Mo Chen
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
| | - Suyong Choi
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
| | - Tianmu Wen
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
| | - Changliang Chen
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
| | - Narendra Thapa
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
| | - Jeong Hyo Lee
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
| | - Vincent L Cryns
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
| | - Richard A Anderson
- University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
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19
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Zhang X, Meng T, Cui S, Liu D, Pang Q, Wang P. Roles of ubiquitination in the crosstalk between tumors and the tumor microenvironment (Review). Int J Oncol 2022; 61:84. [PMID: 35616129 PMCID: PMC9170352 DOI: 10.3892/ijo.2022.5374] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/27/2022] [Indexed: 11/06/2022] Open
Abstract
The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post-translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation-mediated tumor formation, and the function of cancer-associated fibroblasts and infiltrating immune cells (tumor-associated macrophages, T-cells, myeloid-derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.
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Affiliation(s)
- Xiuzhen Zhang
- Anti‑aging and Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Tong Meng
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, P.R. China
| | - Shuaishuai Cui
- School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Dongwu Liu
- Anti‑aging and Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Qiuxiang Pang
- Anti‑aging and Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong 255000, P.R. China
| | - Ping Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, P.R. China
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20
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Wang YH, Sheetz MP. When PIP 2 Meets p53: Nuclear Phosphoinositide Signaling in the DNA Damage Response. Front Cell Dev Biol 2022; 10:903994. [PMID: 35646908 PMCID: PMC9136457 DOI: 10.3389/fcell.2022.903994] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
The mechanisms that maintain genome stability are critical for preventing tumor progression. In the past decades, many strategies were developed for cancer treatment to disrupt the DNA repair machinery or alter repair pathway selection. Evidence indicates that alterations in nuclear phosphoinositide lipids occur rapidly in response to genotoxic stresses. This implies that nuclear phosphoinositides are an upstream element involved in DNA damage signaling. Phosphoinositides constitute a new signaling interface for DNA repair pathway selection and hence a new opportunity for developing cancer treatment strategies. However, our understanding of the underlying mechanisms by which nuclear phosphoinositides regulate DNA damage repair, and particularly the dynamics of those processes, is rather limited. This is partly because there are a limited number of techniques that can monitor changes in the location and/or abundance of nuclear phosphoinositide lipids in real time and in live cells. This review summarizes our current knowledge regarding the roles of nuclear phosphoinositides in DNA damage response with an emphasis on the dynamics of these processes. Based upon recent findings, there is a novel model for p53's role with nuclear phosphoinositides in DNA damage response that provides new targets for synthetic lethality of tumors.
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Affiliation(s)
| | - Michael P. Sheetz
- Biochemistry and Molecular Biology Dept., University of Texas Medical Branch, Galveston, TX, United States
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21
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Liu Y, Wang Y, Li X, Jia Y, Wang J, Ao X. FOXO3a in cancer drug resistance. Cancer Lett 2022; 540:215724. [DOI: 10.1016/j.canlet.2022.215724] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 02/07/2023]
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22
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Ilic VK, Egorova O, Tsang E, Gatto M, Wen Y, Zhao Y, Sheng Y. Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain. Biomolecules 2022; 12:biom12050643. [PMID: 35625571 PMCID: PMC9138535 DOI: 10.3390/biom12050643] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/17/2022] [Accepted: 04/22/2022] [Indexed: 02/04/2023] Open
Abstract
The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Thus, inhibition of MDM2 activity has been pursued as an attractive direction for the development of anti-cancer therapeutics. Virtual screening was performed using the crystal structure of the MDM2-MDMX RING domain dimer against a natural product library and identified a biflavonoid Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment resulted in the downregulation of MDM2 and MDMX and induction of apoptosis in various cancer cell lines. Hinokiflavone demonstrated p53-dependent and -independent tumor-suppressive activity. This report provides biochemical and cellular evidence demonstrating the anti-cancer effects of Hinokiflavone through targeting the MDM2-MDMX RING domain.
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Affiliation(s)
- Viktoria K. Ilic
- Department of Biology, York University, Room 327B Life Science Building, 4700 Keele Street, Toronto, ON M3J 1P3, Canada; (V.K.I.); (O.E.); (E.T.); (M.G.); (Y.W.)
| | - Olga Egorova
- Department of Biology, York University, Room 327B Life Science Building, 4700 Keele Street, Toronto, ON M3J 1P3, Canada; (V.K.I.); (O.E.); (E.T.); (M.G.); (Y.W.)
| | - Ernest Tsang
- Department of Biology, York University, Room 327B Life Science Building, 4700 Keele Street, Toronto, ON M3J 1P3, Canada; (V.K.I.); (O.E.); (E.T.); (M.G.); (Y.W.)
| | - Milena Gatto
- Department of Biology, York University, Room 327B Life Science Building, 4700 Keele Street, Toronto, ON M3J 1P3, Canada; (V.K.I.); (O.E.); (E.T.); (M.G.); (Y.W.)
| | - Yi Wen
- Department of Biology, York University, Room 327B Life Science Building, 4700 Keele Street, Toronto, ON M3J 1P3, Canada; (V.K.I.); (O.E.); (E.T.); (M.G.); (Y.W.)
| | - Yong Zhao
- Beijing Computing Center, Beijing Academy of Science and Technology, Beijing, 100094, China;
| | - Yi Sheng
- Department of Biology, York University, Room 327B Life Science Building, 4700 Keele Street, Toronto, ON M3J 1P3, Canada; (V.K.I.); (O.E.); (E.T.); (M.G.); (Y.W.)
- Correspondence: ; Tel.: 1-416-7362100 (ext. 33521)
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23
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Guo S, Mangal R, Dandu C, Geng X, Ding Y. Role of Forkhead Box Protein O1 (FoxO1) in Stroke: A Literature Review. Aging Dis 2022; 13:521-533. [PMID: 35371601 PMCID: PMC8947839 DOI: 10.14336/ad.2021.0826] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
Stroke is one of the most prevalent causes of death around the world. When a stroke occurs, many cellular signaling cascades and regulators are activated, which results in severe cellular dysfunction and debilitating long-term disability. One crucial regulator of cell fate and function is mammalian Forkhead box protein O1 (FoxO1). Many studies have found FoxO1 to be implicated in many cellular processes, including regulating gluconeogenesis and glycogenolysis. During a stroke, modifications of FoxO1 have been linked to a variety of functions, such as inducing cell death and inflammation, inhibiting oxidative injury, affecting the blood brain barrier (BBB), and regulating hepatic gluconeogenesis. For these functions of FoxO1, different measures and treatments were applied to FoxO1 after ischemia. However, the subtle mechanisms of post-transcriptional modification and the role of FoxO1 are still elusive and even contradictory in the development of stroke. The determination of these mechanisms will lead to further enlightenment for FoxO1 signal transduction and the identification of targeted drugs. The regulation and function of FoxO1 may provide an important way for the prevention and treatment of diseases. Overall, the functions of FoxO1 are multifactorial, and this paper will summarize all of the significant pathways in which FoxO1 plays an important role during stroke damage and recovery.
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Affiliation(s)
- Sichao Guo
- 1Luhe Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China.,3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Ruchi Mangal
- 3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Chaitu Dandu
- 3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Xiaokun Geng
- 1Luhe Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China.,2Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China.,3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Yuchuan Ding
- 3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
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24
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Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol 2022; 14:38-54. [PMID: 35116102 PMCID: PMC8790418 DOI: 10.4251/wjgo.v14.i1.38] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
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Affiliation(s)
- Nirosha J Murugan
- Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
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25
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Abstract
The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.
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26
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Ding L, Zhang Z, Zhao C, Chen L, Chen Z, Zhang J, Liu Y, Nie Y, He Y, Liao K, Zhang X. Ribosomal L1 domain-containing protein 1 coordinates with HDM2 to negatively regulate p53 in human colorectal Cancer cells. J Exp Clin Cancer Res 2021; 40:245. [PMID: 34362424 PMCID: PMC8344204 DOI: 10.1186/s13046-021-02057-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 07/31/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Ribosomal L1 domain-containing protein 1 (RSL1D1) is a nucleolar protein that is essential in cell proliferation. In the current opinion, RSL1D1 translocates to the nucleoplasm under nucleolar stress and inhibits the E3 ligase activity of HDM2 via direct interaction, thereby leading to stabilization of p53. METHODS Gene knockdown was achieved in HCT116p53+/+, HCT116p53-/-, and HCT-8 human colorectal cancer (CRC) cells by siRNA transfection. A lentiviral expression system was used to establish cell strains overexpressing genes of interest. The mRNA and protein levels in cells were evaluated by qRT-PCR and western blot analyses. Cell proliferation, cell cycle, and cell apoptosis were determined by MTT, PI staining, and Annexin V-FITC/PI double staining assays, respectively. The level of ubiquitinated p53 protein was assessed by IP. The protein-RNA interaction was investigated by RIP. The subcellular localization of proteins of interest was determined by IFA. Protein-protein interaction was investigated by GST-pulldown, BiFC, and co-IP assays. The therapeutic efficacy of RSL1D1 silencing on tumor growth was evaluated in HCT116 tumor-bearing nude mice. RESULTS RSL1D1 distributed throughout the nucleus in human CRC cells. Silencing of RSL1D1 gene induced cell cycle arrest at G1/S and cell apoptosis in a p53-dependent manner. RSL1D1 directly interacted with and recruited p53 to HDM2 to form a ternary RSL1D1/HDM2/p53 protein complex and thereby enhanced p53 ubiquitination and degradation, leading to a decrease in the protein level of p53. Destruction of the ternary complex increased the level of p53 protein. RSL1D1 also indirectly decreased the protein level of p53 by stabilizing HDM2 mRNA. Consequently, the negative regulation of p53 by RSL1D1 facilitated cell proliferation and survival and downregulation of RSL1D1 remarkably inhibited the growth of HCT116p53+/+ tumors in a nude mouse model. CONCLUSION We report, for the first time, that RSL1D1 is a novel negative regulator of p53 in human CRC cells and more importantly, a potential molecular target for anticancer drug development.
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Affiliation(s)
- Li Ding
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Zhiping Zhang
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Chenhong Zhao
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Lei Chen
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Zhiqiang Chen
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jie Zhang
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yaxian Liu
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yesen Nie
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yanzhi He
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Kai Liao
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Xinyue Zhang
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, 225009, Jiangsu, China. .,Joint International Research Laboratory of Agriculture & Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou, 225009, Jiangsu, China. .,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, The Ministry of Agriculture of China, Yangzhou University (26116120), Yangzhou, 225009, Jiangsu, China. .,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China.
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27
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Theofani E, Xanthou G. Autophagy: A Friend or Foe in Allergic Asthma? Int J Mol Sci 2021; 22:ijms22126314. [PMID: 34204710 PMCID: PMC8231495 DOI: 10.3390/ijms22126314] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/04/2021] [Accepted: 06/10/2021] [Indexed: 12/20/2022] Open
Abstract
Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease.
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Affiliation(s)
- Efthymia Theofani
- Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11547 Athens, Greece;
- 1st Department of Respiratory Medicine, “Sotiria” Regional Chest Diseases Hospital, Medical School, National Kapodistrian University of Athens, 11547 Athens, Greece
| | - Georgina Xanthou
- Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11547 Athens, Greece;
- Correspondence: ; Tel.: +30-210-65-97-336
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28
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Mathur A, Pandey VK, Khan MF, Kakkar P. PHLPP1/Nrf2-Mdm2 axis induces renal apoptosis via influencing nucleo-cytoplasmic shuttling of FoxO1 during diabetic nephropathy. Mol Cell Biochem 2021; 476:3681-3699. [PMID: 34057658 DOI: 10.1007/s11010-021-04177-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 05/12/2021] [Indexed: 11/30/2022]
Abstract
Impaired PI3K/Akt signaling (insulin resistance) and poor glycemic control (hyperglycemia) are the major risk factors involved in the progression of diabetic nephropathy (DN). This study was designed to identify factors influencing cell survival during DN. We found that high glucose exposure in renal proximal tubular cells (NRK52E) upregulated PHLPP1, an Akt phosphatase (Ser473), causing suppression in Akt and IGF1β phosphorylation leading to inhibition in insulin signaling pathway. Results demonstrate that sustained activation of PHLPP1 promoted nuclear retention of FoxO1 by preventing its ubiquitination via Mdm2, an Akt/ Nrf2-dependent E3 ligase. Thus, enhanced FoxO1 nuclear stability caused aberration in renal gluconeogenesis and activated apoptotic cascade. Conversely, gene silencing of PHLPP1-enhanced Nrf2 expression and attenuated FoxO1 regulated apoptosis compared to hyperglycemic cells. Mechanistic aspects of PHLPP1-Nrf2/FoxO1 signaling were further validated in STZ-nicotinamide-induced type 2 diabetic Wistar rats. Importantly, we observed via immunoblotting and dual immunocytochemical studies that treatment of Morin (2',3,4',5,7-Pentahydroxyflavone) during diabetes significantly augmented FoxO1 nuclear exclusion, resulting in its ubiquitination via Akt-Nrf2/Mdm2 pathway. Furthermore, lowering of PHLPP1 expression by Morin also prevented FoxO1/Mst1-mediated apoptotic signaling in vitro and in vivo. Morin treatment under the experimental conditions, effectively decreased blood glucose levels, ameliorated insulin resistance, alleviated oxidative stress and attenuated renal apoptosis in diabetic rats comparable to metformin thereby exhibiting tremendous potential against renal complications of diabetes. These novel results further acclaim that inhibition of PHLPP1/FoxO1-Mdm2 axis is critical in the pathogenesis of diabetic nephropathy.
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Affiliation(s)
- Alpana Mathur
- Herbal Research Laboratory, Food, Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India
| | - Vivek Kumar Pandey
- Herbal Research Laboratory, Food, Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India.,Academy of Scientific and Innovative Research, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, Uttar Pradesh, India
| | - Mohammad Fareed Khan
- Herbal Research Laboratory, Food, Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India.,Academy of Scientific and Innovative Research, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, Uttar Pradesh, India
| | - Poonam Kakkar
- Herbal Research Laboratory, Food, Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India. .,Academy of Scientific and Innovative Research, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226001, Uttar Pradesh, India.
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29
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Zhang X, Jiang L, Liu H. Forkhead Box Protein O1: Functional Diversity and Post-Translational Modification, a New Therapeutic Target? DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:1851-1860. [PMID: 33976536 PMCID: PMC8106445 DOI: 10.2147/dddt.s305016] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/19/2021] [Indexed: 11/23/2022]
Abstract
Forkhead box protein O1 (FoXO1) is a transcription factor involved in the regulation of a wide variety of physiological process including glucose metabolism, lipogenesis, bone mass, apoptosis, and autophagy. FoXO1 dysfunction is involved in the pathophysiology of various diseases including metabolic diseases, atherosclerosis, and tumors. FoXO1 activity is regulated in response to different physiological or pathogenic conditions by changes in protein expression and post-translational modifications. Various modifications cooperate to regulate FoXO1 activity and FoXO1 target gene transcription. In this review, we summarize how different post-translational modifications regulate FoXO1 physiological function, which may provide new insights for drug design and development.
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Affiliation(s)
- Xiaojun Zhang
- Department of Cardiology, Shandong Rongjun General Hospital, Jinan, 250013, People's Republic of China
| | - Lusheng Jiang
- Department of Emergency, Shandong Rongjun General Hospital, Jinan, 250013, People's Republic of China
| | - Huimin Liu
- Blood Purification Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People's Republic of China
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30
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Shi YY, Meng XT, Xu YN, Tian XJ. Role of FOXO protein's abnormal activation through PI3K/AKT pathway in platinum resistance of ovarian cancer. J Obstet Gynaecol Res 2021; 47:1946-1957. [PMID: 33827148 DOI: 10.1111/jog.14753] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 02/04/2021] [Accepted: 03/05/2021] [Indexed: 01/12/2023]
Abstract
AIM Platinum-based chemotherapy is the standard treatment for ovarian cancer. However, tumor cells' resistance to platinum drugs often occurs. This paper provides a review of Forkhead box O (FOXO) protein's role in platinum resistance of ovarian cancer which hopefully may provide some further guidance for the treatment of platinum-resistant ovarian cancer. METHODS We reviewed a 128 published papers from authoritative and professional journals on FOXO and platinum-resistant ovarian cancer, and adopts qualitative analyses and interpretation based on the literature. RESULTS Ovarian cancer often has abnormal activation of cellular pathways, the most important of which is the PI3K/AKT pathway. FOXOs act as crucial downstream factor of the PI3K/Akt pathway and are negatively regulated by it. DNA damage response and apoptosis including the relationship between FOXOs and ATM-Chk2-p53 are essential for platinum resistance of ovarian cancer. Through gene expression analysis in platinum-resistant ovarian cancer cell model, it was found that FoxO-1 is decreased in platinum-resistant ovarian cancer, so studying the role of FOXO in the pathway on platinum-induced apoptosis may further guide the treatment of platinum-resistant ovarian cancer. CONCLUSIONS There are many drug resistance mechanisms in ovarian cancer, wherein the decrease in cancer cells apoptosis is one of the important causes. Constituted by a series of transcription factors evolving conservatively and mainly working in inhibiting cancer, FOXO proteins play various roles in cells' antitumor response. More and more evidence suggests that we need to re-understand the role that FOXOs have played in cancer development and treatment.
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Affiliation(s)
- Yun-Yue Shi
- Department of Obstetrics and gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiang-Tian Meng
- Department of Ophthalmology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Ya-Nan Xu
- Department of Obstetrics and gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiu-Juan Tian
- Department of Obstetrics and gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
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31
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Li C, Wu Q, Li Z, Wang Z, Tu Y, Chen C, Sun S, Sun S. Exosomal microRNAs in cancer-related sarcopenia: Tumor-derived exosomal microRNAs in muscle atrophy. Exp Biol Med (Maywood) 2021; 246:1156-1166. [PMID: 33554647 DOI: 10.1177/1535370221990322] [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: 12/11/2022] Open
Abstract
Cancer-associated sarcopenia is a complex metabolic syndrome marked by muscle mass wasting. Muscle wasting is a serious complication that is a primary contributor to cancer-related mortality. The underlying molecular mechanisms of cancer-associated sarcopenia have not been completely described to date. In general, evidence shows that the main pathophysiological alterations in sarcopenia are associated with the degradation of cellular components, an exceptional inflammatory secretome and mitochondrial dysfunction. Importantly, we highlight the prospect that several miRNAs carried by tumor-derived exosomes that have shown the ability to promote inflammatory secretion, activate catabolism, and even participate in the regulation of cellular degradation pathways can be delivered to and exert effects on muscle cells. In this review, we aim to describe the current knowledge about the functions of exosomal miRNAs in the induction of cancer-associated muscle wasting and propose potential treatment strategies.
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Affiliation(s)
- Chenyuan Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
| | - Qi Wu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
| | - Zhiyu Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
| | - Zhong Wang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
| | - Yi Tu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
| | - Chuang Chen
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
| | - Si Sun
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
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32
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Kim SJ, Kim KM, Yang JH, Cho SS, Jeong EH, Kim JH, Lee JH, Seo KH, Park EY, Ki SH. Transforming Growth Factor Beta-Induced Foxo3a Acts as a Profibrotic Mediator in Hepatic Stellate Cells. Toxicol Sci 2021; 179:241-250. [PMID: 33372984 DOI: 10.1093/toxsci/kfaa185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Hepatic stellate cells (HSCs) are major contributors to hepatic fibrogenesis facilitating liver fibrosis. Forkhead box O 3a (FoxO3a) is a member of the forkhead transcription factor family, which mediates cell proliferation and differentiation. However, the expression and function of FoxO3a during HSC activation remain largely unknown. FoxO3a overexpression was related to fibrosis in patients, and its expression was colocalized with desmin or α-smooth muscle actin, representative HSC markers. We also observed upregulated FoxO3a levels in two animal hepatic fibrosis models, a carbon tetrachloride-injected model and a bile duct ligation model. In addition, transforming growth factor beta (TGF-β) treatment in mouse primary HSCs or LX-2 cells elevated FoxO3a expression. When FoxO3a was upregulated by TGF-β in LX-2 cells, both the cytosolic and nuclear levels of FoxO3a increased. In addition, we found that the induction of FoxO3a by TGF-β was due to both transcriptional and proteasome-dependent mechanisms. Moreover, FoxO3a overexpression promoted TGF-β-mediated Smad activation. Furthermore, FoxO3a increased fibrogenic gene expression, which was reversed by FoxO3a knockdown. TGF-β-mediated FoxO3a overexpression in HSCs facilitated hepatic fibrogenesis, suggesting that FoxO3a may be a novel target for liver fibrosis prevention and treatment.
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Affiliation(s)
- Seung Jung Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do 58245, Republic of Korea
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Hee Jeong
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Jae Hoon Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Kyu Hwa Seo
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Young Park
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
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33
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Luo B, Wu Y, Liu SL, Li XY, Zhu HR, Zhang L, Zheng F, Liu XY, Guo LY, Wang L, Song HX, Lv YX, Cheng ZS, Chen SY, Wang JN, Tang JM. Vagus nerve stimulation optimized cardiomyocyte phenotype, sarcomere organization and energy metabolism in infarcted heart through FoxO3A-VEGF signaling. Cell Death Dis 2020; 11:971. [PMID: 33184264 PMCID: PMC7665220 DOI: 10.1038/s41419-020-03142-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 12/30/2022]
Abstract
Vagus nerve stimulation (VNS) restores autonomic balance, suppresses inflammation action and minimizes cardiomyocyte injury. However, little knowledge is known about the VNS’ role in cardiomyocyte phenotype, sarcomere organization, and energy metabolism of infarcted hearts. VNS in vivo and acetylcholine (ACh) in vitro optimized the levels of α/β-MHC and α-Actinin positive sarcomere organization in cardiomyocytes while reducing F-actin assembly of cardiomyocytes. Consistently, ACh improved glucose uptake while decreasing lipid deposition in myocytes, correlating both with the increase of Glut4 and CPT1α and the decrease of PDK4 in infarcted hearts in vivo and myocytes in vitro, attributing to improvement in both glycolysis by VEGF-A and lipid uptake by VEGF-B in response to Ach. This led to increased ATP levels accompanied by the repaired mitochondrial function and the decreased oxygen consumption. Functionally, VNS improved the left ventricular performance. In contrast, ACh-m/nAChR inhibitor or knockdown of VEGF-A/B by shRNA powerfully abrogated these effects mediated by VNS. On mechanism, ACh decreased the levels of nuclear translocation of FoxO3A in myocytes due to phosphorylation of FoxO3A by activating AKT. FoxO3A overexpression or knockdown could reverse the specific effects of ACh on the expression of VEGF-A/B, α/β-MHC, Glut4, and CPT1α, sarcomere organization, glucose uptake and ATP production. Taken together, VNS optimized cardiomyocytes sarcomere organization and energy metabolism to improve heart function of the infarcted heart during the process of delaying and/or blocking the switch from compensated hypertrophy to decompensated heart failure, which were associated with activation of both P13K/AKT-FoxO3A-VEGF-A/B signaling cascade.
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Affiliation(s)
- Bin Luo
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, 442000, Hubei, China.,Institute of Biomedicine, Hubei University of Medicine, 442000, Hubei, China
| | - Yan Wu
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, 442000, Hubei, China.,Institute of Biomedicine, Hubei University of Medicine, 442000, Hubei, China
| | - Shu-Lin Liu
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, 442000, Hubei, China.,Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Xing-Yuan Li
- Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Hong-Rui Zhu
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, 442000, Hubei, China
| | - Lei Zhang
- Institute of Biomedicine, Hubei University of Medicine, 442000, Hubei, China.,Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Fei Zheng
- Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Xiao-Yao Liu
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, 442000, Hubei, China
| | - Ling-Yun Guo
- Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Lu Wang
- Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Hong-Xian Song
- Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Yan-Xia Lv
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, 442000, Hubei, China.,Institute of Biomedicine, Hubei University of Medicine, 442000, Hubei, China
| | - Zhong-Shan Cheng
- Applied Bioinformatics Center, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Shi-You Chen
- The Department of Surgery, University of Missouri, Columbia, MO, USA
| | - Jia-Ning Wang
- Institute of Biomedicine, Hubei University of Medicine, 442000, Hubei, China.,Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China
| | - Jun-Ming Tang
- Department of Physiology, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, 442000, Hubei, China. .,Institute of Biomedicine, Hubei University of Medicine, 442000, Hubei, China. .,Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China.
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Kaur N, Raja R, Ruiz-Velasco A, Liu W. Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside. Front Cardiovasc Med 2020; 7:585309. [PMID: 33195472 PMCID: PMC7593653 DOI: 10.3389/fcvm.2020.585309] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022] Open
Abstract
Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.
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Affiliation(s)
- Namrita Kaur
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Rida Raja
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Andrea Ruiz-Velasco
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Wei Liu
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
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35
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Choi HH, Zou S, Wu J, Wang H, Phan L, Li K, Zhang P, Chen D, Liu Q, Qin B, Nguyen TAT, Yeung SJ, Fang L, Lee M. EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2000681. [PMID: 33101846 PMCID: PMC7578864 DOI: 10.1002/advs.202000681] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 08/19/2020] [Indexed: 05/10/2023]
Abstract
Forkhead-Box Class O 4 (FOXO4) is involved in critical biological functions, but its response to EGF-PKB/Akt signal regulation is not well characterized. Here, it is reported that FOXO4 levels are downregulated in response to EGF treatment, with concurrent elevation of COP9 Signalosome subunit 6 (CSN6) and E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) levels. Mechanistic studies show that CSN6 binds and regulates FOXO4 stability through enhancing the E3 ligase activity of COP1, and that COP1 directly interacts with FOXO4 through a VP motif on FOXO4 and accelerates the ubiquitin-mediated degradation of FOXO4. Metabolomic studies demonstrate that CSN6 expression leads to serine and glycine production. It is shown that FOXO4 directly binds and suppresses the promoters of serine-glycine-one-carbon (SGOC) pathway genes, thereby diminishing SGOC metabolism. Evidence shows that CSN6 can regulate FOXO4-mediated SGOC gene expression. Thus, these data suggest a link of CSN6-FOXO4 axis and ser/gly metabolism. Further, it is shown that CSN6-COP1-FOXO4 axis is deregulated in cancer and that the protein expression levels of CSN6 and FOXO4 can serve as prognostic markers for cancers. The results illustrate a pathway regulation of FOXO4-mediated serine/glycine metabolism through the function of CSN6-COP1 axis. Insights into this pathway may be strategically designed for therapeutic intervention in cancers.
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Affiliation(s)
- Hyun Ho Choi
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Shaomin Zou
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Jian‐lin Wu
- State Key Laboratory of Quality Research in Chinese MedicineMacau Institute for Applied Research in Medicine and HealthMacau University of Science and TechnologyMacao999078China
| | - Huashe Wang
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Liem Phan
- Department of Molecular and Cellular OncologyDivision of Basic Science ResearchThe University of Texas MD Anderson Cancer CenterHoustonTX77030USA
| | - Kai Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Peng Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Daici Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Qingxin Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Baifu Qin
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | | | - Sai‐Ching J. Yeung
- Department of Emergency MedicineDivision of Internal MedicineThe University of Texas MD Anderson Cancer CenterHoustonTX77030USA
| | - Lekun Fang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Mong‐Hong Lee
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
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The Roles of Ubiquitin in Mediating Autophagy. Cells 2020; 9:cells9092025. [PMID: 32887506 PMCID: PMC7564124 DOI: 10.3390/cells9092025] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/25/2020] [Accepted: 08/28/2020] [Indexed: 12/20/2022] Open
Abstract
Ubiquitination, the post-translational modification essential for various intracellular processes, is implicated in multiple aspects of autophagy, the major lysosome/vacuole-dependent degradation pathway. The autophagy machinery adopted the structural architecture of ubiquitin and employs two ubiquitin-like protein conjugation systems for autophagosome biogenesis. Ubiquitin chains that are attached as labels to protein aggregates or subcellular organelles confer selectivity, allowing autophagy receptors to simultaneously bind ubiquitinated cargos and autophagy-specific ubiquitin-like modifiers (Atg8-family proteins). Moreover, there is tremendous crosstalk between autophagy and the ubiquitin-proteasome system. Ubiquitination of autophagy-related proteins or regulatory components plays significant roles in the precise control of the autophagy pathway. In this review, we summarize and discuss the molecular mechanisms and functions of ubiquitin and ubiquitination, in the process and regulation of autophagy.
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Abstract
Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
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Affiliation(s)
- Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
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Modulation of DNA Damage Response by Sphingolipid Signaling: An Interplay that Shapes Cell Fate. Int J Mol Sci 2020; 21:ijms21124481. [PMID: 32599736 PMCID: PMC7349968 DOI: 10.3390/ijms21124481] [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: 04/16/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/11/2022] Open
Abstract
Although once considered as structural components of eukaryotic biological membranes, research in the past few decades hints at a major role of bioactive sphingolipids in mediating an array of physiological processes including cell survival, proliferation, inflammation, senescence, and death. A large body of evidence points to a fundamental role for the sphingolipid metabolic pathway in modulating the DNA damage response (DDR). The interplay between these two elements of cell signaling determines cell fate when cells are exposed to metabolic stress or ionizing radiation among other genotoxic agents. In this review, we aim to dissect the mediators of the DDR and how these interact with the different sphingolipid metabolites to mount various cellular responses.
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Sica V, Bravo-San Pedro JM, Izzo V, Pol J, Pierredon S, Enot D, Durand S, Bossut N, Chery A, Souquere S, Pierron G, Vartholomaiou E, Zamzami N, Soussi T, Sauvat A, Mondragón L, Kepp O, Galluzzi L, Martinou JC, Hess-Stumpp H, Ziegelbauer K, Kroemer G, Maiuri MC. Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate. Cell Rep 2020; 27:820-834.e9. [PMID: 30995479 DOI: 10.1016/j.celrep.2019.03.058] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 01/25/2019] [Accepted: 03/15/2019] [Indexed: 12/28/2022] Open
Abstract
Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens.
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Affiliation(s)
- Valentina Sica
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Jose Manuel Bravo-San Pedro
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Valentina Izzo
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Jonathan Pol
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Sandra Pierredon
- Department of Cell Biology, University of Geneva, 1211 Geneva, Switzerland
| | - David Enot
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Sylvère Durand
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Noélie Bossut
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Alexis Chery
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Sylvie Souquere
- CNRS-UMR-9196, Institut Gustave Roussy, 94805 Villejuif, France
| | - Gerard Pierron
- CNRS-UMR-9196, Institut Gustave Roussy, 94805 Villejuif, France
| | | | - Naoufal Zamzami
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Thierry Soussi
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, 17176 Stockholm, Sweden
| | - Allan Sauvat
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Laura Mondragón
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Oliver Kepp
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Lorenzo Galluzzi
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA
| | | | | | - Karl Ziegelbauer
- Research & Development, Pharmaceuticals, Bayer AG, 42117 Wuppertal, Germany
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden.
| | - Maria Chiara Maiuri
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France.
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Wang Y, Qiu W, Liu N, Sun L, Liu Z, Wang S, Wang P, Liu S, Lv J. Forkhead box K1 regulates the malignant behavior of gastric cancer by inhibiting autophagy. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:107. [PMID: 32175400 DOI: 10.21037/atm.2019.12.123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Forkhead box K1 (FOXK1) is a transcription factor that contributes to cancer development, but it is unclear how FOXK1 regulates the proliferation and migration of gastric cancer (GC) cells. The purpose of this study was to investigate the clinical significance, biological function, and molecular mechanisms of FOXK1 in GC. Methods We conducted bioinformatics assays and western blotting to assess FOXK1 expression. Then, we performed immunohistochemistry (IHC) with tissue microarrays (TMAs) to assess FOXK1 expression in order to identify an association between FOXK1 expression levels and clinical parameters. We used 5-ethynyl-2'-deoxyuridine (EdU), wound healing and Transwell assays to determine whether FOXK1 promotes malignant behaviors in GC. Furthermore, immunofluorescence staining, transmission electron microscopy and western blotting were used to verify an association between FOXK1 and autophagy. Results We observed high levels of FOXK1 expression in GC tissues, which were associated with the degree of malignancy in GC. FOXK1 promotes the malignant behavior of GC by regulating autophagy via activation of the class I phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and inhibition of the expression of class III PI3K. Conclusions These findings provide a new target for the comprehensive treatment of GC by highlighting the relationship between FOXK1 and malignant behaviors in GC.
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Affiliation(s)
- Yixuan Wang
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Wensheng Qiu
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Ning Liu
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Libin Sun
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Zhao Liu
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Shasha Wang
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Peng Wang
- Department of Oncology, Weifang Yidu Central Hospital, Qingzhou 262500, China
| | - Shihai Liu
- Central Laboratory, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Jing Lv
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
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Yin Y, Wang J, Zhao X, Wu X, Zou H, Qin Z, Cao J. Overexpressed FOXO3 improves inflammatory status in mice by affecting NLRP3-mediated cell coronation in necrotizing colitis mice. Biomed Pharmacother 2020; 125:109867. [PMID: 32058213 DOI: 10.1016/j.biopha.2020.109867] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/08/2020] [Accepted: 01/10/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE To investigate the relationship between FOXO3 overexpression and NLRP3 and explore the effect of FOXO3 on necrotizing colitis. METHODS 100 clean grade newborn SD (Sprague Dawley) rats were randomly divided into 4 groups: NEC group, NEC + FOXO3a group, NEC + NC group and control group. NEC rat model was established by hypoxia + hypothermia stimulation; HE staining was used for detection of the inflammation of intestinal tissue. The histological scores of intestinal tissues were histologically scored, generally, there were three types of inflammatory scoring systems including anatomically based systems, severity-based systems and quality of life systems (Lim et al., 2015) and in this study we utilized severity-based systems by HE staining. Human intestinal epithelial cell line was transfected with recombinant plasmid overexpressing FOXO3a and recombinant plasmid overexpressing NLRP3, and divided into control group, LPS group, LPS + NC group, LPS + FOXO3a group and LPS + FOXO3a + NLRP3 group; Caspase-1 was used for the detection of pyroptosis. The expressions of FOXO3a, NLRP3, cleaved Caspase-1 and the expression of TLR4 in TLR4 signaling pathway were detected by RT-qPCR and WB. IL-1β, IL-6, IL-18 and TNF-α were detected by ELISA. RESULTS (1) FOXO3a is under-expressed and NLRP3 is highly expressed in NEC neonatal rat intestinal tissue. (2) The inflammatory condition of intestinal tissue in NEC + FOXO3a group was improved compared with NEC group (P < 0.05). (3) FOXO3a was highly expressed in NEC + FOXO3a group. The expression of IL-1β, IL-6, IL-18, SOD and MDA in NEC + FOXO3a group was lower than that in NEC group. (4) The expression of IL-1β, IL-6, IL-18, SOD and MDA in intestinal epithelial cells of LPS + FOXO3a group was lower than other groups. (5) Overexpression of FOXO3a inhibits LPS-induced pyroptotic cell death in intestinal epithelial cells by inhibiting NLRP3. CONCLUSION Overexpression of FOXO3 in mice with necrotizing colitis can improve inflammatory conditions in mice by affecting NLRP3-mediated cell caking.
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Affiliation(s)
- Yiyu Yin
- Department of General Surgery, Xuzhou Children's Hospital, Xuzhou Medical University, China
| | - Jian Wang
- Department of General Surgery, Children's Hospital of Soochow University, China
| | - Xiaodong Zhao
- Department of Paediatrics, Nantong First People's Hospital, China
| | - Xiaole Wu
- Department of Anesthesiology, Xuzhou Children's Hospital, Xuzhou Medical University, China
| | - Huaxin Zou
- Department of General Surgery, Xuzhou Children's Hospital, Xuzhou Medical University, China
| | - Zhenfang Qin
- Department of General Surgery, Xuzhou Children's Hospital, Xuzhou Medical University, China
| | - Junhua Cao
- Department of Emergency Medicine, Xuzhou Children's Hospital, Xuzhou Medical University, China.
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42
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Lam B, Roudier E. Considering the Role of Murine Double Minute 2 in the Cardiovascular System? Front Cell Dev Biol 2020; 7:320. [PMID: 31921839 PMCID: PMC6916148 DOI: 10.3389/fcell.2019.00320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/21/2019] [Indexed: 01/26/2023] Open
Abstract
The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.
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Affiliation(s)
- Brian Lam
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
| | - Emilie Roudier
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
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43
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A Review of FoxO1-Regulated Metabolic Diseases and Related Drug Discoveries. Cells 2020; 9:cells9010184. [PMID: 31936903 PMCID: PMC7016779 DOI: 10.3390/cells9010184] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/08/2020] [Accepted: 01/08/2020] [Indexed: 12/11/2022] Open
Abstract
FoxO1 is a conserved transcription factor involved in energy metabolism. It is tightly regulated by modifications on its mRNA and protein and responds to environmental nutrient signals. FoxO1 controls the transcription of downstream genes mediating metabolic regulation. Dysfunction of FoxO1 pathways results in several metabolic diseases, including diabetes, obesity, non-alcoholic fatty liver disease, and atherosclerosis. Here, we summarize the mechanism of FoxO1 regulation behind these diseases and FoxO1-related drug discoveries.
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Hasmatali JCD, De Guzman J, Johnston JM, Noyan H, Juurlink BH, Misra V, Verge VMK. FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury. Neural Regen Res 2020; 15:2353-2361. [PMID: 32594060 PMCID: PMC7749464 DOI: 10.4103/1673-5374.284999] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Emerging evidence supports that the stress response to peripheral nerve injury extends beyond the injured neuron, with alterations in associated transcription factors detected both locally and remote to the lesion. Stress-induced nuclear translocation of the transcription factor forkhead class box O3a (FOXO3a) was initially linked to activation of apoptotic genes in many neuronal subtypes. However, a more complex role of FOXO3a has been suggested in the injury response of sensory neurons, with the injured neuron expressing less FOXO3a. To elucidate this response and test whether non-injured sensory neurons also alter FOXO3a expression, the temporal impact of chronic unilateral L4–6 spinal nerve transection on FOXO3a expression and nuclear localization in adult rat dorsal root ganglion neurons ipsilateral, contralateral or remote to injury relative to naïve controls was examined. In naïve neurons, high cytoplasmic and nuclear levels of FOXO3a colocalized with calcitonin gene related peptide, a marker of the nociceptive subpopulation. One hour post-injury, an acute increase in nuclear FOXO3a in small size injured neurons occurred followed by a significant decrease after 1, 2 and 4 days, with levels increasing toward pre-injury levels by 1 week post-injury. A more robust biphasic response to the injury was observed in uninjured neurons contralateral to and those remote to injury. Nuclear levels of FOXO3a peaked at 1 day, decreased by 4 days, then increased by 1 week post-injury, a response mirrored in C4 dorsal root ganglion neurons remote to injury. This altered expression contralateral and remote to injury supports that spinal nerve damage has broader systemic impacts, a response we recently reported for another stress transcription factor, Luman/CREB3. The early decreased expression and nuclear localization of FOXO3a in the injured neuron implicate these changes in the cell body response to injury that may be protective. Finally, the broader systemic changes support the existence of stress/injury-induced humeral factor(s) influencing transcriptional and potentially behavioral changes in uninjured dorsal root ganglion neurons. Approval to conduct this study was obtained from the University of Saskatchewan Animal Research Ethics Board (protocol #19920164).
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Affiliation(s)
- Jovan C D Hasmatali
- Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center; Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK; Current affiliation: Department of Critical Care Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Jolly De Guzman
- Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada
| | - Jayne M Johnston
- Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada
| | - Hossein Noyan
- Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK; Current affiliation: Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada
| | - Bernhard H Juurlink
- Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada
| | - Vikram Misra
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Valerie M K Verge
- Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada
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Wang B, Li Y, Wang H, Zhao J, Zhao Y, Liu Z, Ma H. FOXO3a is stabilized by USP18-mediated de-ISGylation and inhibits TGF-β1-induced fibronectin expression. J Investig Med 2019; 68:786-791. [PMID: 31874933 PMCID: PMC7057795 DOI: 10.1136/jim-2019-001145] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2019] [Indexed: 12/16/2022]
Abstract
FOXO3a belongs to a family of transcription factors characterized by a conserved forkhead box DNA-binding domain. It has been known to regulate various cellular processes including cell proliferation, apoptosis and differentiation. Post-translational modifications of FOXO3a and their roles in the regulation of FOXO3a activity have been well-documented. FOXO3a can be phosphorylated, acetylated and ubiquitinated, however, the ISGylation of FOXO3a has not been reported. Protein overexpression, ISGylation and half-life were measured to determine the post-translational modification of FOXO3a. Human fibroblast cells were treated with transforming growth factor (TGF)-β1 to determine the role of FOXO3a ISGylation in TGF-β1 signaling. FOXO3a’s half-life is around 3.7 hours. Inhibition of the proteasome, not lysosome, extends its half-life. ISGylation, but not ubiquitination of FOXO3a, is increased in the presence of the proteasome inhibitor. Overexpression of ISG15 increases FOXO3a degradation, while overexpression of USP18 stabilizes FOXO3a through de-ISGylation. These results suggest that FOXO3a is degraded in the ISGylation and proteasome system, which can be reversed by USP18, an ISG15-specific deubiquitinase. This study reveals a new molecular mechanism by which ISGylation regulates FOXO3a degradation. Furthermore, we show that the overexpression of FOXO3a attenuated TGF-β1-induced fibronectin expression in human lung fibroblast cells without altering Smad2/3 expression and activation. FOXO3a can be ISGylated, which can regulate FOXO3a stability. USP18/FOXO3a pathway is a potential target for treating TGF-β1-mediated fibrotic diseases such as idiopathic pulmonary fibrosis.
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Affiliation(s)
- Ban Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yanhui Li
- Department of Anesthesia, Jilin University First Hospital, Changchun, China.,Department of Physiology and Cell Biology, Ohio State University, Columbus, Ohio, USA
| | - Heather Wang
- Department of Physiology and Cell Biology, Ohio State University, Columbus, Ohio, USA
| | - Jing Zhao
- Department of Physiology and Cell Biology, Ohio State University, Columbus, Ohio, USA
| | - Yutong Zhao
- Department of Physiology and Cell Biology, Ohio State University, Columbus, Ohio, USA
| | - Zhonghui Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Haichun Ma
- Department of Anesthesia, Jilin University First Hospital, Changchun, China
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Cramer D, Mazur J, Espinosa O, Schlesner M, Hübschmann D, Eils R, Staub E. Genetic Interactions and Tissue Specificity Modulate the Association of Mutations with Drug Response. Mol Cancer Ther 2019; 19:927-936. [PMID: 31826931 DOI: 10.1158/1535-7163.mct-19-0045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 06/21/2019] [Accepted: 12/04/2019] [Indexed: 11/16/2022]
Abstract
In oncology, biomarkers are widely used to predict subgroups of patients that respond to a given drug. Although clinical decisions often rely on single gene biomarkers, machine learning approaches tend to generate complex multi-gene biomarkers that are hard to interpret. Models predicting drug response based on multiple altered genes often assume that the effects of single alterations are independent. We asked whether the association of cancer driver mutations with drug response is modulated by other driver mutations or the tissue of origin. We developed an analytic framework based on linear regression to study interactions in pharmacogenomic data from two large cancer cell line panels. Starting from a model with only covariates, we included additional variables only if they significantly improved simpler models. This allows to systematically assess interactions in small, easily interpretable models. Our results show that including mutation-mutation interactions in drug response prediction models tends to improve model performance and robustness. For example, we found that TP53 mutations decrease sensitivity to BRAF inhibitors in BRAF-mutated cell lines and patient tumors, suggesting a therapeutic benefit of combining inhibition of oncogenic BRAF with reactivation of the tumor suppressor TP53. Moreover, we identified tissue-specific mutation-drug associations and synthetic lethal triplets where the simultaneous mutation of two genes sensitizes cells to a drug. In summary, our interaction-based approach contributes to a holistic view on the determining factors of drug response.
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Affiliation(s)
- Dina Cramer
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,Oncology Bioinformatics, Merck KGaA, Darmstadt, Germany
| | - Johanna Mazur
- Oncology Bioinformatics, Merck KGaA, Darmstadt, Germany
| | | | - Matthias Schlesner
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel Hübschmann
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Pediatric Immunology, Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany.,Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Roland Eils
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Health Data Science Unit, Bioquant, Medical Faculty, Heidelberg University, Heidelberg, Germany.,Center for Digital Health, Berlin Institute of Health and Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Eike Staub
- Oncology Bioinformatics, Merck KGaA, Darmstadt, Germany
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Wang W, Qin JJ, Rajaei M, Li X, Yu X, Hunt C, Zhang R. Targeting MDM2 for novel molecular therapy: Beyond oncology. Med Res Rev 2019; 40:856-880. [PMID: 31587329 DOI: 10.1002/med.21637] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.
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Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.,Drug Discovery Institute, University of Houston, Houston, Texas
| | - Jiang-Jiang Qin
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Mehrdad Rajaei
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Xin Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Xiaoyi Yu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Courtney Hunt
- Drug Discovery Institute, University of Houston, Houston, Texas
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.,Drug Discovery Institute, University of Houston, Houston, Texas
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49
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Di Malta C, Cinque L, Settembre C. Transcriptional Regulation of Autophagy: Mechanisms and Diseases. Front Cell Dev Biol 2019; 7:114. [PMID: 31312633 PMCID: PMC6614182 DOI: 10.3389/fcell.2019.00114] [Citation(s) in RCA: 190] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 06/05/2019] [Indexed: 12/18/2022] Open
Abstract
Macro (Autophagy) is a catabolic process that relies on the cooperative function of two organelles: the lysosome and the autophagosome. The recent discovery of a transcriptional gene network that co-regulates the biogenesis and function of these two organelles, and the identification of transcription factors, miRNAs and epigenetic regulators of autophagy, demonstrated that this catabolic process is controlled by both transcriptional and post-transcriptional mechanisms. In this review article, we discuss the nuclear events that control autophagy, focusing particularly on the role of the MiT/TFE transcription factor family. In addition, we will discuss evidence suggesting that the transcriptional regulation of autophagy could be targeted for the treatment of human genetic diseases, such as lysosomal storage disorders (LSDs) and neurodegeneration.
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Affiliation(s)
- Chiara Di Malta
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
- Department of Medical and Translational Sciences, University of Naples Federico II, Naples, Italy
| | - Laura Cinque
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Carmine Settembre
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
- Department of Medical and Translational Sciences, University of Naples Federico II, Naples, Italy
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50
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Investigating Mechanisms that Control Ubiquitin-Mediated DAF-16/FOXO Protein Turnover. Methods Mol Biol 2019. [PMID: 30414143 DOI: 10.1007/978-1-4939-8900-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
Protein turnover of FOXO family transcription factors is regulated by the ubiquitin-proteasome system. A complex interplay of factors that covalently attach certain types of ubiquitin chains (E3-ubiquitin ligases), and enzymes that are able to remove ubiquitin conjugates (deubiquitylases), regulate the degradation of FOXO proteins by the proteasome. Here, we describe methods to characterize candidate E3-ubiquitin ligases and deubiquitylases as regulators of the FOXO ubiquitylation status. Our protocol can be utilized to purify and enrich a ubiquitylated FOXO pool from cultured cells under denaturing conditions, which inactivates cellular deubiquitylases and thereby protects ubiquitin conjugates on FOXO proteins. In addition, our method describes how ubiquitylated FOXO proteins can be renatured in a stepwise fashion to serve as substrates for in vitro deubiquitylation (DUB) assays.
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