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Gyi KK, Anuchapreeda S, Intasai N, Tungjai M, Okonogi S, Iwasaki A, Usuki T, Tima S. Anti-leukemia activity of the ethyl acetate extract from Gynostemma pentaphyllum (Thunb.) leaf against FLT3-overexpressing AML cells and its phytochemical characterization. BMC Complement Med Ther 2025; 25:172. [PMID: 40361130 PMCID: PMC12076849 DOI: 10.1186/s12906-025-04903-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Gynostemma pentaphyllum (Thunb.), a traditional adaptogenic herb, is known for its bioactive components with potential anti-cancer properties. Acute myeloid leukemia (AML) progression is significantly influenced by Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3) signaling, while Wilms' tumor 1 (WT1) serves as a key prognostic marker. This study investigates the anti-leukemia activities of active G. pentaphyllum leaf extracts and their components, focusing on the inhibition of FLT3 and WT1 activity. METHODS G. pentaphyllum extracts were prepared through maceration, yielding three crude fractional extracts. The cytotoxicity of the extracts was screened against various leukemia cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The most cytotoxic extract was further fractionated and purified via column chromatography. The anti-proliferative and apoptotic induction activities of the active extract and its fraction were evaluated through cell cycle and apoptosis analyses using flow cytometry. Changes in mitochondrial membrane potential (ΔΨm) were assessed by spectrofluorometry. To confirm anti-leukemia activity, the expression levels of FLT3, WT1 and apoptotic-related protein were analyzed using Western blotting. The major active compounds within the active fractions were identified and characterized using Electrospray Ionization Mass Spectrometry (ESI-MS) and Nuclear Magnetic Resonance (NMR) spectroscopy. RESULTS The ethyl acetate fractional extract (F-EtOAc) demonstrated the highest cytotoxicity, particularly against FLT3-overexpressing EoL-1 (IC50 = 40.82 ± 0.8 µg/mL) and MV4-11 (IC50 = 35.54 ± 4.1 µg/mL) AML cell lines. Fraction F10 was identified as the most active fraction, significantly inhibited FLT3 and WT1 protein expression and induced G0/G1 cell cycle arrest in a dose-dependent manner. Additionally, F10 induced dose-dependent apoptosis through disruption of ΔΨm, p53 up-regulation and caspase-3 activation. Further purification of F10 identified dehydrovomifoliol as its major bioactive compound. CONCLUSION These findings suggest that the ethyl acetate extract of G. pentaphyllum contains bioactive compounds with anti-leukemia potential, warranting further investigation to evaluate its efficacy against AML. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Khin Khin Gyi
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
- Faculty of Associated Medical Sciences, Chiang Mai University, Under The CMU Presidential Scholarship, Chiang Mai, 50200, Thailand
- Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo, 102-8554, Japan
| | - Songyot Anuchapreeda
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cancer Research Unit of Associated Medical Sciences (AMS CRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nutjeera Intasai
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cancer Research Unit of Associated Medical Sciences (AMS CRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Montree Tungjai
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn Okonogi
- Center of Excellence in Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai, 50200, Thailand
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Arihiro Iwasaki
- Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo, 112-8551, Japan
| | - Toyonobu Usuki
- Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo, 102-8554, Japan.
| | - Singkome Tima
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Cancer Research Unit of Associated Medical Sciences (AMS CRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Center of Excellence in Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Mertz TM, Kockler ZW, Coxon M, Cordero C, Raval AK, Brown AJ, Harcy V, Gordenin DA, Roberts SA. Defining APOBEC-induced mutation signatures and modifying activities in yeast. Methods Enzymol 2025; 713:115-161. [PMID: 40250951 DOI: 10.1016/bs.mie.2024.11.041] [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] [Indexed: 04/20/2025]
Abstract
APOBEC cytidine deaminases guard cells in a variety of organisms from invading viruses and foreign nucleic acids. Recently, several human APOBECs have been implicated in mutating evolving cancer genomes. Expression of APOBEC3A and APOBEC3B in yeast allowed experimental derivation of the substitution patterns they cause in dividing cells, which provided critical links to these enzymes in the etiology of the COSMIC single base substitution (SBS) signatures 2 and 13 in human tumors. Additionally, the ability to scale yeast experiments to high-throughput screens allows use of this system to also investigate cellular pathways impacting the frequency of APOBEC-induced mutation. Here, we present validated methods utilizing yeast to determine APOBEC mutation signatures, genetic interactors, and chromosomal substrate preferences. These methods can be employed to assess the potential of other human APOBECs and APOBEC orthologs in different species to contribute to cancer genome evolution as well as define the pathways that protect the nuclear genome from inadvertent APOBEC activity during viral restriction.
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Affiliation(s)
- Tony M Mertz
- Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont, Burlington, VT, United States
| | - Zachary W Kockler
- Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC, United States
| | - Margo Coxon
- School of Molecular Biosciences, Washington State University, Pullman, WA, United States
| | - Cameron Cordero
- Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont, Burlington, VT, United States
| | - Atri K Raval
- Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont, Burlington, VT, United States
| | - Alexander J Brown
- School of Molecular Biosciences, Washington State University, Pullman, WA, United States
| | - Victoria Harcy
- School of Molecular Biosciences, Washington State University, Pullman, WA, United States
| | - Dmitry A Gordenin
- Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC, United States
| | - Steven A Roberts
- Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont, Burlington, VT, United States.
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Ma DD, Shi WJ, Lu ZJ, Zhang JG, Hu LX, Huang Z, Li SY, Long XB, Liu X, Huang CS, Ying GG. Antitussive drug dextromethorphan induces developmental impairment in zebrafish. JOURNAL OF HAZARDOUS MATERIALS 2025; 486:137042. [PMID: 39742866 DOI: 10.1016/j.jhazmat.2024.137042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/16/2024] [Accepted: 12/29/2024] [Indexed: 01/04/2025]
Abstract
Dextromethorphan (DXM) is a common ingredient in cough and cold remedies. Despite its widespread presence in aquatic environments, the impact of DXM on fish remains largely unknown. This study evaluated the developmental impairment of zebrafish embryos exposed to DXM from 2 hours post-fertilization (hpf) to 14 days post-fertilization (dpf) at five different exposure concentrations: 0.06, 0.61, 8.12, 76.3, and 827 μg/L. Results indicated a concentration-dependent increase in bioconcentration of DXM at 7 dpf and 14 dpf. The LC50 at 14 dpf was 93.3 μg/L, demonstrating DXM has a high toxicity to zebrafish larvae. Additionally, DXM reduced body length and heart rate, and elevated malformation in a dose-dependent manner in larvae at 72 hpf, 7 dpf and 14 dpf. Biochemical analysis (DNA conformations and 8-hydroxy-2deoxyguanosine level) and transcriptomic analysis (DNA damage and cell cycle) indicated that DXM triggered DNA damage in larvae. Concurrently, DXM triggered DNA damage response (e.g., cell cycle arrest, DNA repair failure, and cell apoptosis) in larvae at 7 dpf and 14 dpf. These results help explain DXM caused severe developmental impairment via DNA damage-related pathways in zebrafish larvae, highlighting the importance of focusing on ecological and public health risks of DXM in natural environment.
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Affiliation(s)
- Dong-Dong Ma
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Wen-Jun Shi
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China.
| | - Zhi-Jie Lu
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Jin-Ge Zhang
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Li-Xin Hu
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Zheng Huang
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Si-Ying Li
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Xiao-Bing Long
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Xin Liu
- Anti-Drug Technology Center of Guangdong Province and National Anti-Drug Laboratory Guangdong Regional Center, Guangdong Provincial Key Laboratory of Psychoactive Substances Monitoring and Safety, Guangzhou 510230, China
| | - Chu-Shu Huang
- Anti-Drug Technology Center of Guangdong Province and National Anti-Drug Laboratory Guangdong Regional Center, Guangdong Provincial Key Laboratory of Psychoactive Substances Monitoring and Safety, Guangzhou 510230, China
| | - Guang-Guo Ying
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China; Anti-Drug Technology Center of Guangdong Province and National Anti-Drug Laboratory Guangdong Regional Center, Guangdong Provincial Key Laboratory of Psychoactive Substances Monitoring and Safety, Guangzhou 510230, China.
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Gui Z, Shi W, Zhou F, Yan Y, Li Y, Xu Y. The role of estrogen receptors in intracellular estrogen signaling pathways, an overview. J Steroid Biochem Mol Biol 2025; 245:106632. [PMID: 39551163 DOI: 10.1016/j.jsbmb.2024.106632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/29/2024] [Accepted: 11/09/2024] [Indexed: 11/19/2024]
Abstract
To date five members of estrogen receptors (ESRs) have been reported. They are grouped into two classes, the nuclear estrogen receptors are members of the nuclear receptor family which found at nuclear, cytoplasm and plasma membrane, and the membrane estrogen receptors, such as G protein-coupled estrogen receptor 1, ESR-X and Gq-coupled membrane estrogen receptor. The structure and function of estrogen receptors, and interaction between ESR and coregulators were reviewed. In canonical pathway ESRs can translocate to the nucleus, bind to the target gene promotor with or without estrogen responsive element and regulate transcription, mediating the genomic effects of estrogen. Coactivators and corepressors are recruited to activate or inhibit transcription by activated ESRs. Many coactivators and corepressors are recruited to activate or inhibit ESR mediated gene transcription via different mechanisms. ESRs also indirectly bind to the promoter via interaction with other transcription factors, tethering the transcription factors. ESRs can be phosphorylated by several kinases such as p38, extracellular-signal-regulated kinase, and activated protein kinase B, and which activates transcription without ligand binding. Non-genomic estrogen action can be manifested by the increases of cytoplasmic NO and Ca2+ through the activation of membrane ESRs. In female, ESRs signaling is crucial for folliculogenesis, oocyte growth, ovulation, oviduct and uterus. In male, ESRs signaling modulates libido, erectile function, leydig cell steroidogenesis, sertoli cell's function, and epididymal fluid homeostatsis, supporting spermatogenesis and sperm maturation. The abnormal ESRs signaling is believed to be closely related to reproductive diseases and cancer.
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Affiliation(s)
- Zichang Gui
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China.
| | - Wei Shi
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Fangting Zhou
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Yongqing Yan
- Yunnan Dasheng Biotechnology Co., LTD, Yuxi 653100, China.
| | - Yuntian Li
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Yang Xu
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China; Yunnan Dasheng Biotechnology Co., LTD, Yuxi 653100, China.
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Kumar P, Hassan M, Tacke F, Engelmann C. Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes. Cell Mol Life Sci 2024; 81:200. [PMID: 38684535 PMCID: PMC11058795 DOI: 10.1007/s00018-024-05230-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 03/11/2024] [Accepted: 04/07/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND AND AIM Cellular senescence of hepatocytes involves permanent cell cycle arrest, disrupted cellular bioenergetics, resistance to cell death, and the release of pro-inflammatory cytokines. This 'zombie-like' state perpetuates harmful effects on tissues and holds potential implications for liver disease progression. Remarkably, senescence exhibits heterogeneity, stemming from two crucial factors: the inducing stressor and the cell type. As such, our present study endeavors to characterize stressor-specific changes in senescence phenotype, its related molecular patterns, and cellular bioenergetics in primary mouse hepatocytes (PMH) and hepatocyte-derived liver organoids (HepOrgs). METHODS PMH, isolated by collagenase-perfused mouse liver (C57B6/J; 18-23 weeks), were cultured overnight in William's E-medium supplemented with 2% FBS, L-glutamine, and hepatocyte growth supplements. HepOrgs were developed by culturing cells in a 3D matrix for two weeks. The senescence was induced by DNA damage (doxorubicin, cisplatin, and etoposide), oxidative stress (H2O2, and ethanol), and telomere inhibition (BIBR-1532), p53 activation (nutlin-3a), DNA methyl transferase inhibition (5-azacitidine), and metabolism inhibitors (galactosamine and hydroxyurea). SA-β galactosidase activity, immunofluorescence, immunoblotting, and senescence-associated secretory phenotype (SASP), and cellular bioenergetics were used to assess the senescence phenotype. RESULTS Each senescence inducer triggers a unique combination of senescence markers in hepatocytes. All senescence inducers, except hydroxyurea and ethanol, increased SA-β galactosidase activity, the most commonly used marker for cellular senescence. Among the SASP factors, CCL2 and IL-10 were consistently upregulated, while Plasminogen activator inhibitor-1 exhibited global downregulation across all modes of senescence. Notably, DNA damage response was activated by DNA damage inducers. Cell cycle markers were most significantly reduced by doxorubicin, cisplatin, and galactosamine. Additionally, DNA damage-induced senescence shifted cellular bioenergetics capacity from glycolysis to oxidative phosphorylation. In HepOrgs exposed to senescence inducers, there was a notable increase in γH2A.X, p53, and p21 levels. Interestingly, while showing a similar trend, SASP gene expression in HepOrgs was significantly higher compared to PMH, demonstrating a several-fold increase. CONCLUSION In our study, we demonstrated that each senescence inducer activates a unique combination of senescence markers in PMH. Doxorubicin demonstrated the highest efficacy in inducing senescence, followed by cisplatin and H2O2, with no impact on apoptosis. Each inducer prompted DNA damage response and mitochondrial dysfunction, independent of MAPK/AKT.
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Affiliation(s)
- Pavitra Kumar
- Department of Hepatology and Gastroenterology, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Augustenburger Platz 1, Forum 4, Raum 2.0704a, 13353, Berlin, Germany
| | - Mohsin Hassan
- Department of Hepatology and Gastroenterology, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Augustenburger Platz 1, Forum 4, Raum 2.0704a, 13353, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Augustenburger Platz 1, Forum 4, Raum 2.0704a, 13353, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Augustenburger Platz 1, Forum 4, Raum 2.0704a, 13353, Berlin, Germany.
- Berlin Institute of Health (BIH), 10178, Berlin, Germany.
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Rizzo MG, Best TM, Huard J, Philippon M, Hornicek F, Duan Z, Griswold AJ, Kaplan LD, Hare JM, Kouroupis D. Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents. Cells 2023; 12:1421. [PMID: 37408255 PMCID: PMC10217382 DOI: 10.3390/cells12101421] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/08/2023] [Accepted: 05/13/2023] [Indexed: 07/07/2023] Open
Abstract
Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is rising, likely due to the increase in obesity and post-traumatic osteoarthritis (PTOA). In recent years, due to a better understanding of the underlying pathophysiology of OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. In particular, the role of inflammation and the immune system has been increasingly recognized as important in a variety of musculoskeletal diseases, including OA. Similarly, higher levels of host cellular senescence, characterized by cessation of cell division and the secretion of a senescence-associated secretory phenotype (SASP) within the local tissue microenvironments, have also been linked to OA and its progression. New advances in the field, including stem cell therapies and senolytics, are emerging with the goal of slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are a subset of multipotent adult stem cells that have demonstrated the potential to modulate unchecked inflammation, reverse fibrosis, attenuate pain, and potentially treat patients with OA. Numerous studies have demonstrated the potential of MSC extracellular vesicles (EVs) as cell-free treatments that comply with FDA regulations. EVs, including exosomes and microvesicles, are released by numerous cell types and are increasingly recognized as playing a critical role in cell-cell communication in age-related diseases, including OA. Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of SASP. This article highlights the encouraging potential for MSC or MSC-derived products alone or in combination with senolytics to control patient symptoms and potentially mitigate the progression of OA. We will also explore the application of genomic principles to the study of OA and the potential for the discovery of OA phenotypes that can motivate more precise patient-driven treatments.
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Affiliation(s)
- Michael G. Rizzo
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Johnny Huard
- Center for Regenerative and Personalized Medicine (CRPM), Steadman Philippon Research Institute, Vail, CO 81657, USA (M.P.)
| | - Marc Philippon
- Center for Regenerative and Personalized Medicine (CRPM), Steadman Philippon Research Institute, Vail, CO 81657, USA (M.P.)
| | - Francis Hornicek
- Department of Orthopedics, Sarcoma Biology Laboratory, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.H.); (Z.D.)
| | - Zhenfeng Duan
- Department of Orthopedics, Sarcoma Biology Laboratory, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.H.); (Z.D.)
| | - Anthony J. Griswold
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA;
| | - Lee D. Kaplan
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Malter JS. Pin1 and Alzheimer's disease. Transl Res 2023; 254:24-33. [PMID: 36162703 PMCID: PMC10111655 DOI: 10.1016/j.trsl.2022.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/29/2022] [Accepted: 09/19/2022] [Indexed: 10/14/2022]
Abstract
Alzheimer's disease (AD) is an immense and growing public health crisis. Despite over 100 years of investigation, the etiology remains elusive and therapy ineffective. Despite current gaps in knowledge, recent studies have identified dysfunction or loss-of-function of Pin1, a unique cis-trans peptidyl prolyl isomerase, as an important step in AD pathogenesis. Here I review the functionality of Pin1 and its role in neurodegeneration.
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Affiliation(s)
- James S Malter
- Department of Pathology, UT Southwestern Medical Center, 5333 Harry Hines Blvd, Dallas, TX 75390.
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Ruggieri L, Moretti A, Berardi R, Cona MS, Dalu D, Villa C, Chizzoniti D, Piva S, Gambaro A, La Verde N. Host-Related Factors in the Interplay among Inflammation, Immunity and Dormancy in Breast Cancer Recurrence and Prognosis: An Overview for Clinicians. Int J Mol Sci 2023; 24:4974. [PMID: 36902406 PMCID: PMC10002538 DOI: 10.3390/ijms24054974] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
A significant proportion of patients treated for early breast cancer develop medium-term and late distant recurrence. The delayed manifestation of metastatic disease is defined as "dormancy". This model describes the aspects of the clinical latency of isolated metastatic cancer cells. Dormancy is regulated by extremely complex interactions between disseminated cancer cells and the microenvironment where they reside, the latter in turn influenced directly by the host. Among these entangled mechanisms, inflammation and immunity may play leading roles. This review is divided into two parts: the first describes the biological underpinnings of cancer dormancy and the role of the immune response, in particular, for breast cancer; the second provides an overview of the host-related factors that may influence systemic inflammation and immune response, subsequently impacting the dynamics of breast cancer dormancy. The aim of this review is to provide physicians and medical oncologists a useful tool to understand the clinical implications of this relevant topic.
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Affiliation(s)
- Lorenzo Ruggieri
- Medical Oncology Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi, n° 74, 20157 Milan, Italy
| | - Anna Moretti
- Medical Oncology Unit, S. Carlo Hospital, ASST Santi Paolo e Carlo, 20153 Milan, Italy
| | - Rossana Berardi
- Department of Oncology, Università Politecnica delle Marche—AOU delle Marche, 60121 Ancona, Italy
| | - Maria Silvia Cona
- Medical Oncology Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi, n° 74, 20157 Milan, Italy
| | - Davide Dalu
- Medical Oncology Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi, n° 74, 20157 Milan, Italy
| | - Cecilia Villa
- Medical Oncology Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi, n° 74, 20157 Milan, Italy
| | - Davide Chizzoniti
- Medical Oncology Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi, n° 74, 20157 Milan, Italy
| | - Sheila Piva
- Medical Oncology Unit, Fatebenefratelli Hospital, ASST Fatebenefratelli-Sacco, 20157 Milan, Italy
| | - Anna Gambaro
- Medical Oncology Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi, n° 74, 20157 Milan, Italy
| | - Nicla La Verde
- Medical Oncology Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Via G.B. Grassi, n° 74, 20157 Milan, Italy
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Clay DE, Fox DT. DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond. Genes (Basel) 2021; 12:1882. [PMID: 34946831 PMCID: PMC8701014 DOI: 10.3390/genes12121882] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/25/2022] Open
Abstract
Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected.
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Affiliation(s)
- Delisa E. Clay
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA;
| | - Donald T. Fox
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA;
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
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10
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Li BS, Jin AL, Zhou Z, Seo JH, Choi BM. DRG2 Accelerates Senescence via Negative Regulation of SIRT1 in Human Diploid Fibroblasts. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:7301373. [PMID: 34777693 PMCID: PMC8580627 DOI: 10.1155/2021/7301373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 10/04/2021] [Indexed: 11/21/2022]
Abstract
Accumulating evidence suggests that developmentally regulated GTP-binding protein 2 (DRG2), an evolutionarily conserved GTP-binding protein, plays an important role in regulating cell growth, inflammation, and mitochondria dynamics. However, the effect of DRG2 in aging remains unclear. In this study, we found that endogenous DRG2 protein expression is upregulated in oxidative stress-induced premature senescence models and tissues of aged mice. Ectopic expression of DRG2 significantly promoted senescence-associated β-galactosidase (SA-β-gal) activity and inhibited cell growth, concomitant with increase in levels of acetyl (ac)-p53 (Lys382), ac-nuclear factor-kB (NF-κB) p65 (Lys310), p21 Waf1/Cip1 , and p16 Ink4a and a decrease in cyclin D1. In this process, reactive oxygen species (ROS) and phosphorylation of H2A histone family member X (H2A.X), forming γ-H2A.X, were enhanced. Mechanistically, ectopic expression of DRG2 downregulated Sirtuin-1 (SIRT1), resulting in augmented acetylation of p53 and NF-κB p65. Additionally, DRG2 knockdown significantly abolished oxidative stress-induced premature senescence. Our results provide a possible molecular mechanism for investigation of cellular senescence and aging regulated by DRG2.
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Affiliation(s)
- Bing Si Li
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - Ai Lin Jin
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - ZiQi Zhou
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - Jae Ho Seo
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
- Sarcopenia Total Solution Center, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
| | - Byung-Min Choi
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
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11
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Na HJ, Akan I, Abramowitz LK, Hanover JA. Nutrient-Driven O-GlcNAcylation Controls DNA Damage Repair Signaling and Stem/Progenitor Cell Homeostasis. Cell Rep 2021; 31:107632. [PMID: 32402277 DOI: 10.1016/j.celrep.2020.107632] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/27/2020] [Accepted: 04/21/2020] [Indexed: 12/20/2022] Open
Abstract
Stem/progenitor cells exhibit high proliferation rates, elevated nutrient uptake, altered metabolic flux, and stress-induced genome instability. O-GlcNAcylation is an essential post-translational modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which act in a nutrient- and stress-responsive manner. The precise role of O-GlcNAc in adult stem cells and the relationship between O-GlcNAc and the DNA damage response (DDR) is poorly understood. Here, we show that hyper-O-GlcNacylation leads to elevated insulin signaling, hyperproliferation, and DDR activation that mimic the glucose- and oxidative-stress-induced response. We discover a feedback mechanism involving key downstream effectors of DDR, ATM, ATR, and CHK1/2 that regulates OGT stability to promote O-GlcNAcylation and elevate DDR. This O-GlcNAc-dependent regulatory pathway is critical for maintaining gut homeostasis in Drosophila and the DDR in mouse embryonic stem cells (ESCs) and mouse embryonic fibroblasts (MEFs). Our findings reveal a conserved mechanistic link among O-GlcNAc cycling, stem cell self-renewal, and DDR with profound implications for stem-cell-derived diseases including cancer.
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Affiliation(s)
- Hyun-Jin Na
- Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ilhan Akan
- Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lara K Abramowitz
- Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - John A Hanover
- Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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12
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Soni A, Mladenov E, Iliakis G. Proficiency in homologous recombination repair is prerequisite for activation of G 2-checkpoint at low radiation doses. DNA Repair (Amst) 2021; 101:103076. [PMID: 33640756 DOI: 10.1016/j.dnarep.2021.103076] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/30/2020] [Accepted: 02/13/2021] [Indexed: 10/22/2022]
Abstract
Pathways of repair of DNA double strand breaks (DSBs) cooperate with DNA damage cell cycle checkpoints to safeguard genomic stability when cells are exposed to ionizing radiation (IR). It is widely accepted that checkpoints facilitate the function of DSB repair pathways. Whether DSB repair proficiency feeds back into checkpoint activation is less well investigated. Here, we study activation of the G2-checkpoint in cells deficient in homologous recombination repair (HRR) after exposure to low IR doses (∼1 Gy) in the G2-phase. We report that in the absence of functional HRR, activation of the G2-checkpoint is severely impaired. This response is specific for HRR, as cells deficient in classical non-homologous end joining (c-NHEJ) develop a similar or stronger G2-checkpoint than wild-type (WT) cells. Inhibition of ATM or ATR leaves largely unaffected residual G2-checkpoint in HRR-deficient cells, suggesting that the G2-checkpoint engagement of ATM/ATR is coupled to HRR. HRR-deficient cells show in G2-phase reduced DSB-end-resection, as compared to WT-cells or c-NHEJ mutants, confirming the reported link between resection and G2-checkpoint activation. Strikingly, at higher IR doses (≥4 Gy) HRR-deficient cells irradiated in G2-phase activate a weak but readily detectable ATM/ATR-dependent G2-checkpoint, whereas HRR-deficient cells irradiated in S-phase develop a stronger G2-checkpoint than WT-cells. We conclude that HRR and the ATM/ATR-dependent G2-checkpoint are closely intertwined in cells exposed to low IR-doses in G2-phase, where HRR dominates; they uncouple as HRR becomes suppressed at higher IR doses. Notably, this coupling is specific for cells irradiated in G2-phase, and cells irradiated in S-phase utilize a different mechanistic setup.
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Affiliation(s)
- Aashish Soni
- Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122, Essen, Germany
| | - Emil Mladenov
- Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122, Essen, Germany
| | - George Iliakis
- Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122, Essen, Germany.
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13
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Werner S, Heidrich I, Pantel K. Clinical management and biology of tumor dormancy in breast cancer. Semin Cancer Biol 2021; 78:49-62. [PMID: 33582172 DOI: 10.1016/j.semcancer.2021.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/05/2021] [Accepted: 02/03/2021] [Indexed: 01/08/2023]
Abstract
Clinical tumor dormancy is specified as an extended latency period between removal of the primary tumor and subsequent relapse in a cancer patient who has been clinically disease-free. In particular, patients with estrogen receptor-positive breast cancer can undergo extended periods of more than five years before they relapse with overt metastatic disease. Recent studies have shown that minimal residual disease in breast cancer patients can be monitored by different liquid biopsy approaches like analysis of circulating tumor cells or cell-free tumor DNA. Even though the biological principles underlying tumor dormancy in breast cancer patients remain largely unknown, clinical observations and experimental studies have identified emerging mechanisms that control the state of tumor dormancy. In this review, we illustrate the latest discoveries on different molecular aspects that contribute to the control of tumor dormancy and distant metastatic relapse, then discuss current treatments affecting minimal residual disease and dormant cancer cells, and finally highlight how novel liquid biopsy based diagnostic methodologies can be integrated into the detection and molecular characterization of minimal residual disease.
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Affiliation(s)
- Stefan Werner
- Institute for Tumor Biology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany; Mildred-Scheel-Nachwuchszentrum HaTRiCs4, Universitäres Cancer Center Hamburg, Germany
| | - Isabel Heidrich
- Institute for Tumor Biology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Klaus Pantel
- Institute for Tumor Biology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
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14
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Konzman D, Abramowitz LK, Steenackers A, Mukherjee MM, Na HJ, Hanover JA. O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability. Front Genet 2020; 11:605263. [PMID: 33329753 PMCID: PMC7719714 DOI: 10.3389/fgene.2020.605263] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Cellular identity in multicellular organisms is maintained by characteristic transcriptional networks, nutrient consumption, energy production and metabolite utilization. Integrating these cell-specific programs are epigenetic modifiers, whose activity is often dependent on nutrients and their metabolites to function as substrates and co-factors. Emerging data has highlighted the role of the nutrient-sensing enzyme O-GlcNAc transferase (OGT) as an epigenetic modifier essential in coordinating cellular transcriptional programs and metabolic homeostasis. OGT utilizes the end-product of the hexosamine biosynthetic pathway to modify proteins with O-linked β-D-N-acetylglucosamine (O-GlcNAc). The levels of the modification are held in check by the O-GlcNAcase (OGA). Studies from model organisms and human disease underscore the conserved function these two enzymes of O-GlcNAc cycling play in transcriptional regulation, cellular plasticity and mitochondrial reprogramming. Here, we review these findings and present an integrated view of how O-GlcNAc cycling may contribute to cellular memory and transgenerational inheritance of responses to parental stress. We focus on a rare human genetic disorder where mutant forms of OGT are inherited or acquired de novo. Ongoing analysis of this disorder, OGT- X-linked intellectual disability (OGT-XLID), provides a window into how epigenetic factors linked to O-GlcNAc cycling may influence neurodevelopment.
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Affiliation(s)
| | | | | | | | | | - John A. Hanover
- Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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15
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Fang Y, Zhang Z. Arsenic trioxide as a novel anti-glioma drug: a review. Cell Mol Biol Lett 2020; 25:44. [PMID: 32983240 PMCID: PMC7517624 DOI: 10.1186/s11658-020-00236-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/15/2020] [Indexed: 02/08/2023] Open
Abstract
Arsenic trioxide has shown a strong anti-tumor effect with little toxicity when used in the treatment of acute promyelocytic leukemia (APL). An effect on glioma has also been shown. Its mechanisms include regulation of apoptosis and autophagy; promotion of the intracellular production of reactive oxygen species, causing oxidative damage; and inhibition of tumor stem cells. However, glioma cells and tissues from other sources show different responses to arsenic trioxide. Researchers are working to enhance its efficacy in anti-glioma treatments and reducing any adverse reactions. Here, we review recent research on the efficacy and mechanisms of action of arsenic trioxide in the treatment of gliomas to provide guidance for future studies.
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Affiliation(s)
- Yi Fang
- Department of Ultrasound, First Affiliated Hospital of China Medical University, Shenyang, 110001 Liaoning People's Republic of China
| | - Zhen Zhang
- Department of Ultrasound, First Affiliated Hospital of China Medical University, Shenyang, 110001 Liaoning People's Republic of China
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16
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Hussain SS, Zhang F, Zhang Y, Thakur K, Naudhani M, Cespedes-Acuña CL, Wei Z. Stevenleaf from Gynostemma Pentaphyllum inhibits human hepatoma cell (HepG2) through cell cycle arrest and apoptotic induction. FOOD SCIENCE AND HUMAN WELLNESS 2020. [DOI: 10.1016/j.fshw.2020.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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17
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Miao ZF, Lewis MA, Cho CJ, Adkins-Threats M, Park D, Brown JW, Sun JX, Burclaff JR, Kennedy S, Lu J, Mahar M, Vietor I, Huber LA, Davidson NO, Cavalli V, Rubin DC, Wang ZN, Mills JC. A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle. Dev Cell 2020; 55:178-194.e7. [PMID: 32768422 DOI: 10.1016/j.devcel.2020.07.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/04/2020] [Accepted: 07/11/2020] [Indexed: 02/06/2023]
Abstract
Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term "paligenosis" to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifrd1-/- cells do not complete paligenosis because persistent p53 prevents mTORC1 reactivation and cell proliferation. Ddit4-/- cells never suppress mTORC1 and bypass the IFRD1 checkpoint on proliferation. Previous reports and our current data implicate DDIT4/IFRD1 in governing paligenosis in multiple organs and species. Thus, we propose that an evolutionarily conserved, dedicated molecular network has evolved to allow differentiated cells to re-enter the cell cycle (i.e., undergo paligenosis) after tissue injury. VIDEO ABSTRACT.
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Affiliation(s)
- Zhi-Feng Miao
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang 110001, China
| | - Mark A Lewis
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Charles J Cho
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Mahliyah Adkins-Threats
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Dongkook Park
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jeffrey W Brown
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jing-Xu Sun
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang 110001, China
| | - Joseph R Burclaff
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Susan Kennedy
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jianyun Lu
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Marcus Mahar
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
| | - Ilja Vietor
- Division of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Lukas A Huber
- Division of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Nicholas O Davidson
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Valeria Cavalli
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
| | - Deborah C Rubin
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang 110001, China.
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
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18
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Dai L, Qureshi AR, Witasp A, Lindholm B, Stenvinkel P. Early Vascular Ageing and Cellular Senescence in Chronic Kidney Disease. Comput Struct Biotechnol J 2019; 17:721-729. [PMID: 31303976 PMCID: PMC6603301 DOI: 10.1016/j.csbj.2019.06.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 06/08/2019] [Accepted: 06/11/2019] [Indexed: 01/08/2023] Open
Abstract
Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by progressive vascular disease, systemic inflammation, muscle wasting and frailty. The predominant early vascular ageing (EVA) process mediated by medial vascular calcification (VC) results in a marked discrepancy between chronological and biological vascular age in CKD. Though the exact underlying mechanisms of VC and EVA are not fully elucidated, accumulating evidence indicates that cellular senescence - and subsequent chronic inflammation through the senescence-associated secretary phenotype (SASP) - plays a fundamental role in its initiation and progression. In this review, we discuss the pathophysiological links between senescence and the EVA process in CKD, with focus on cellular senescence and media VC, and potential anti-ageing therapeutic strategies of senolytic drugs targeting cellular senescence and EVA in CKD.
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Affiliation(s)
| | | | | | | | - Peter Stenvinkel
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
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19
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Wang Y, Wang S, Song R, Cai J, Xu J, Tang X, Li N. Ginger polysaccharides induced cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Int J Biol Macromol 2019; 123:81-90. [PMID: 30414900 DOI: 10.1016/j.ijbiomac.2018.10.169] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 10/19/2018] [Accepted: 10/24/2018] [Indexed: 01/22/2023]
Abstract
In this study, ginger polysaccharide (GP) was obtained from ginger by enzymatic method, its chemical properties and antitumor activity were investigated. The results indicated that the composition and proportion of GP were l‑rhamnose, d‑arabinose, d‑mannose, d‑glucose and d‑galactose in a molar ratio of 3.64:5.37:3.04:61.03:26.91, GP had the characteristic absorption peak of polysaccharide. Congo red experiment showed that GP had a triple helix structure, which could have anti-tumor effect. Furthermore, MTT assay, cell morphology observation, nuclear morphology observation and reactive oxygen species observation demonstrated that GP had significant antitumor effect. Flow cytometry suggested that GP could promote apoptosis and arrest cells in G0-G1 phase. Real-time fluorescence quantification and Western blot revealed that GP could up-regulate the expression of Bax, Fas, FasL, caspase-3, p21 and p53, and down-regulate the expression of Bcl-2. These studies suggested that GP would be used as an antitumor drug in foods to promote the development of functional foods.
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Affiliation(s)
- Yun Wang
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Shengxuan Wang
- College of Animal and Veterinary medicine, Shandong Agricultural University, Tai'an 271018, PR China
| | - Rongzhen Song
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Jingjing Cai
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Jingjing Xu
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Xiaozhen Tang
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China.
| | - Ningyang Li
- Key Laboratory of Food Processing Technology and Quality Control in Shandong Province, College of Food Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China.
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20
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Anufrieva KS, Shender VO, Arapidi GP, Lagarkova MA, Govorun VM. The Diverse Roles of Spliceosomal Proteins in the Regulation of Cell Processes. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2019. [DOI: 10.1134/s1068162019010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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21
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Yao J, Xiao J, Wei X, Lu Y. Chaetominine induces cell cycle arrest in human leukemia K562 and colon cancer SW1116 cells. Oncol Lett 2018; 16:4671-4678. [PMID: 30214601 PMCID: PMC6126184 DOI: 10.3892/ol.2018.9161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 11/21/2017] [Indexed: 02/05/2023] Open
Abstract
Chaetominine is a cytotoxic alkaloid that has been demonstrated to promote apoptotic cell death in human leukemia K562 cells. In the present study, chaetominine inhibited K562 (IC50 34 nM) and SW1116 (IC50 46 nM) cell growth. However, it remains unclear whether the inhibition of cell growth is associated with the cell cycle. To assess this potential relationship, the effect of chaetominine on the cell cycle of K562 and SW1116 cells was examined. Chaetominine treatment caused cell apoptosis and G1-phase arrest in SW1116 cells. Conversely, K562 cells underwent S-phase arrest according to flow cytometric analysis. The present study also aimed to elucidate the molecular mechanisms underpinning cell cycle regulation following the incubation of the associated cells with chaetominine. Western blot and reverse transcription-quantitative polymerase chain reaction analyses suggested that chaetominine treatment facilitated the expression of p53, p21, checkpoint kinase 2 (Chk2) and phosphorylated ataxia telangiectasia mutated (p-ATM) and caused a reduction in the mRNA levels of cyclin E and cyclin-dependent kinases (CDKs) 2 and 4. These results suggest that chaetominine may be involved in the regulation of p53/p21 and ATM and Rad3-related (ATM)/Chk2 signaling in SW1116 cells. Previous studies have demonstrated that these signaling pathways are responsible for G1-phase arrest. Results of the present study demonstrated that the expression of p-ATR and Chk1 were increased in K562 cells. Additionally, cdc25A levels were decreased, while protein and gene expression levels of cyclin A and CDK2 were repressed. These results elucidated the role of chaetominine in in the regulation of ATR/cdc25A/Chk1 expression in K562 cells. These proteins are thus important determinants in the initiation of S-phase arrest. These data support the hypothesis that chaetominine is a potential anti-cancer therapeutic agent that targets the cell cycle.
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Affiliation(s)
- Jingyun Yao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, P.R. China
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, P.R. China
| | - Jianbo Xiao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau 999078, P.R. China
| | - Xing Wei
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, P.R. China
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, P.R. China
| | - Yanhua Lu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, P.R. China
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, P.R. China
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22
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Abstract
Senescence is a double-edged sword that can function in opposite directions. It is a potential mechanism for a cell to avoid malignant transformation. However, senescence can also promote cancer development by altering the cellular microenvironment through a senescence-associated secretory phenotype (SASP). At least, three types of cellular stress such as activation of oncogenes, loss of tumor suppressor genes, and chemo/radiotherapy can induce cell senescence. Oncogene-induced senescence can be intertwiningly associated with the replicative senescence. Early-stage senescence may protect cell from transformation, while prolonged senescence often promotes cancer development. This review will focus on the characteristics of senescence, discuss the regulation of senescence during cancer development, and highlight the complexity of senescence that makes cancer treatment challenging.
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Affiliation(s)
- Sulin Zeng
- Department of Microbiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.,Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY, USA
| | - Wen H Shen
- Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY, USA
| | - Li Liu
- Department of Microbiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
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23
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Park JS, Jeon HJ, Pyo JH, Kim YS, Yoo MA. Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in Drosophila. Aging (Albany NY) 2018; 10:322-338. [PMID: 29514136 PMCID: PMC5892683 DOI: 10.18632/aging.101390] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 02/23/2018] [Indexed: 09/29/2023]
Abstract
Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells' environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of Mre11, Rad50, Nbs1, ATM, ATR, Chk1, and Chk2, which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult fly's survival. Our data indicated a distinct effect of DDR depletion in stem or niche cells on tissue-resident stem cell proliferation. Our findings provide evidence of the essential role of DDR in protecting EC against ISC aging, thus providing a better understanding of the molecular mechanisms of stem cell/niche aging.
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Affiliation(s)
- Joung-Sun Park
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
- Equal contribution
| | - Ho-Jun Jeon
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
- Equal contribution
| | - Jung-Hoon Pyo
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Young-Shin Kim
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Mi-Ae Yoo
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
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Chen H, Wang P, Du Z, Wang G, Gao S. Oxidative stress, cell cycle arrest, DNA damage and apoptosis in adult zebrafish (Danio rerio) induced by tris(1,3-dichloro-2-propyl) phosphate. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2018; 194:37-45. [PMID: 29149642 DOI: 10.1016/j.aquatox.2017.11.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 10/31/2017] [Accepted: 11/01/2017] [Indexed: 06/07/2023]
Abstract
Tris(1,3-dichloro-2-propyl)phosphate (TDCPP) is an additive flame retardant of high production volume, and frequently detected in biota and environment. However, knowledge on its potential risk and toxicological mechanism still remains limited. In this study, DNA damage, transcriptomic responses and biochemical changes in the liver of zebrafish (Danio rerio) induced by TDCPP were investigated. Zebrafish was exposed to 45.81μg/L (1/100 (96h-LC50)) and 229.05μg/L (1/20 (96h-LC50)) TDCPP for 7 d. The reactive oxygen species (ROS) and GSH contents, in addition to antioxidant enzyme activities in the liver changed significantly, and the mRNA levels of genes related to oxidative stress were alerted in a dose-dependent and/or sex-dependent manner after exposure to TDCPP. Significant DNA damage in zebrafish liver was found, and olive tail moment increased in a concentration-dependent manner. Moreover, exposure of TDCPP at 45.81μg/L level activated the cell cycle arrest, DNA repair system and apoptosis pathway in male zebrafish, and 229.05μg/L TDCPP exposure inhibited those pathways in both male and female zebrafish. The cell apoptosis was confirmed in TUNEL assay as higher incidence of TUNEL-positive cells were observed in zebrafish exposed to 229.05μg/L TDCPP. Our results also indicated that males were more sensitive to TDCPP exposure compared with females. Taken together, our results showed that TDCPP could induce oxidative stress, cell cycle arrest, DNA damage and apoptosis in adult zebrafish liver in sex- and concentration-dependent manners.
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Affiliation(s)
- Hanyan Chen
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210093, China
| | - Pingping Wang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210093, China
| | - Zhongkun Du
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210093, China
| | - Guowei Wang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210093, China
| | - Shixiang Gao
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210093, China.
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25
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Gidfar S, Milani FY, Milani BY, Shen X, Eslani M, Putra I, Huvard MJ, Sagha H, Djalilian AR. Rapamycin Prolongs the Survival of Corneal Epithelial Cells in Culture. Sci Rep 2017; 7:40308. [PMID: 28054657 PMCID: PMC5215596 DOI: 10.1038/srep40308] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 12/06/2016] [Indexed: 01/08/2023] Open
Abstract
Rapamycin has previously been shown to have anti-aging effects in cells and organisms. These studies were undertaken to investigate the effects of rapamycin on primary human corneal epithelial cells in vitro. Cell growth and viability were evaluated by bright field microscopy. Cell proliferation and cycle were evaluated by flow cytometry. The expression of differentiation markers was evaluated by quantitative PCR and Western blot. Senescence was evaluated by senescence-associated β-Galactosidase staining and by Western blot analysis of p16. Apoptosis was evaluated by a TUNEL assay. The results demonstrated that primary HCEC treated with rapamycin had lower proliferation but considerably longer survival in vitro. Rapamycin-treated cells maintained a higher capacity to proliferate after removal of rapamycin and expressed more keratin 14, N-Cadherin, DeltaNp63 and ABCG2, and less keratin 12, consistent with their less differentiated state. Rapamycin treated cells demonstrated less senescence by X-β-Gal SA staining and by lower expression of p16. Apoptosis was also lower in the rapamycin treated cells. These results indicate that rapamycin treatment of HCEC prevents the loss of corneal epithelial stem/progenitor cells to replicative senescence and apoptosis. Rapamycin may be a useful additive for ex vivo expansion of corneal epithelial cells.
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Affiliation(s)
- Sanaz Gidfar
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Farnoud Y Milani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Behrad Y Milani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Xiang Shen
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Medi Eslani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Ilham Putra
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Michael J Huvard
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Hossein Sagha
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago IL, USA
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26
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Moureau S, Luessing J, Harte EC, Voisin M, Lowndes NF. A role for the p53 tumour suppressor in regulating the balance between homologous recombination and non-homologous end joining. Open Biol 2016; 6:rsob.160225. [PMID: 27655732 PMCID: PMC5043586 DOI: 10.1098/rsob.160225] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 08/25/2016] [Indexed: 12/24/2022] Open
Abstract
Loss of p53, a transcription factor activated by cellular stress, is a frequent event in cancer. The role of p53 in tumour suppression is largely attributed to cell fate decisions. Here, we provide evidence supporting a novel role for p53 in the regulation of DNA double-strand break (DSB) repair pathway choice. 53BP1, another tumour suppressor, was initially identified as p53 Binding Protein 1, and has been shown to inhibit DNA end resection, thereby stimulating non-homologous end joining (NHEJ). Yet another tumour suppressor, BRCA1, reciprocally promotes end resection and homologous recombination (HR). Here, we show that in both human and mouse cells, the absence of p53 results in impaired 53BP1 focal recruitment to sites of DNA damage induced by ionizing radiation. This effect is largely independent of cell cycle phase and the extent of DNA damage. In p53-deficient cells, diminished localization of 53BP1 is accompanied by a reciprocal increase in BRCA1 recruitment to DSBs. Consistent with these findings, we demonstrate that DSB repair via NHEJ is abrogated, while repair via homology-directed repair (HDR) is stimulated. Overall, we propose that in addition to its role as an ‘effector’ protein in the DNA damage response, p53 plays a role in the regulation of DSB repair pathway choice.
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Affiliation(s)
- Sylvie Moureau
- Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland
| | - Janna Luessing
- Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland
| | - Emma Christina Harte
- Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland
| | - Muriel Voisin
- Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland
| | - Noel Francis Lowndes
- Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland
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Francica P, Aebersold DM, Medová M. Senescence as biologic endpoint following pharmacological targeting of receptor tyrosine kinases in cancer. Biochem Pharmacol 2016; 126:1-12. [PMID: 27574725 DOI: 10.1016/j.bcp.2016.08.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 08/25/2016] [Indexed: 12/11/2022]
Abstract
Cellular senescence was first described in 1961 in a seminal study by Hayflick and Moorhead as a limit to the replicative lifespan of somatic cells after serial cultivation. Since then, major advances in our understanding of senescence have been achieved suggesting that this mechanism is activated also by oncogenic stimuli, oxidative stress and DNA damage, giving rise to the concept of premature senescence. Regardless of the initial trigger, numerous experimental observations have been provided to support the notion that both replicative and premature senescence play pivotal roles in early stages of tumorigenesis and in response of tumor cells to anticancer treatments. Moreover, various studies have suggested that the induction of senescence by both chemo- and radiotherapy in a variety of cancer types correlates with treatment outcome. As it is widely accepted that cellular senescence may function as a fundamental barrier of tumor progression, the significance of senescence for clinical interventions that make use of novel molecular targeting-based modalities needs to be well defined. Interestingly, despite numerous studies evaluating efficacies of receptor tyrosine kinases (RTKs) targeting strategies in both preclinical and clinical settings, the relevance of RTKs inhibition-associated senescence in tumors remains less characterized. Here we review the available literature that describes premature senescence as a major mechanism following targeting of RTKs in preclinical as well as in clinical settings. Additionally, we discuss the possible role of diverse RTKs in regulating the induction of senescence following cellular stress and possible implications of this crosstalk in identification of biomarkers of inhibitor-mediated chemo- and radiosensitization approaches.
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Affiliation(s)
- Paola Francica
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3008 Bern, Switzerland
| | - Daniel M Aebersold
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3008 Bern, Switzerland
| | - Michaela Medová
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
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28
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Feng C, Liu H, Yang M, Zhang Y, Huang B, Zhou Y. Disc cell senescence in intervertebral disc degeneration: Causes and molecular pathways. Cell Cycle 2016; 15:1674-84. [PMID: 27192096 PMCID: PMC4957599 DOI: 10.1080/15384101.2016.1152433] [Citation(s) in RCA: 215] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The accumulation of senescent disc cells in degenerative intervertebral disc (IVD) suggests the detrimental roles of cell senescence in the pathogenesis of intervertebral disc degeneration (IDD). Disc cell senescence decreased the number of functional cells in IVD. Moreover, the senescent disc cells were supposed to accelerate the process of IDD via their aberrant paracrine effects by which senescent cells cause the senescence of neighboring cells and enhance the matrix catabolism and inflammation in IVD. Thus, anti-senescence has been proposed as a novel therapeutic target for IDD. However, the development of anti-senescence therapy is based on our understanding of the molecular mechanism of disc cell senescence. In this review, we focused on the molecular mechanism of disc cell senescence, including the causes and various molecular pathways. We found that, during the process of IDD, age-related damages together with degenerative external stimuli activated both p53-p21-Rb and p16-Rb pathways to induce disc cell senescence. Meanwhile, disc cell senescence was regulated by multiple signaling pathways, suggesting the complex regulating network of disc cell senescence. To understand the mechanism of disc cell senescence better contributes to developing the anti-senescence-based therapies for IDD.
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Affiliation(s)
- Chencheng Feng
- a Department of Orthopedics , Xinqiao Hospital, Third Military Medical University , Chongqing , People's Republic of China
| | - Huan Liu
- a Department of Orthopedics , Xinqiao Hospital, Third Military Medical University , Chongqing , People's Republic of China
| | - Minghui Yang
- a Department of Orthopedics , Xinqiao Hospital, Third Military Medical University , Chongqing , People's Republic of China
| | - Yang Zhang
- a Department of Orthopedics , Xinqiao Hospital, Third Military Medical University , Chongqing , People's Republic of China
| | - Bo Huang
- a Department of Orthopedics , Xinqiao Hospital, Third Military Medical University , Chongqing , People's Republic of China
| | - Yue Zhou
- a Department of Orthopedics , Xinqiao Hospital, Third Military Medical University , Chongqing , People's Republic of China
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Abstract
The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy.
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Affiliation(s)
- Penny A Jeggo
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK
| | - Laurence H Pearl
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK
| | - Antony M Carr
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK
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30
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Zhang E, Guo Q, Gao H, Xu R, Teng S, Wu Y. Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway. PLoS One 2015; 10:e0143814. [PMID: 26629991 PMCID: PMC4668014 DOI: 10.1371/journal.pone.0143814] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 11/10/2015] [Indexed: 12/18/2022] Open
Abstract
Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as "metabolic memory." Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how "metabolic memory" would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement of SIRT1 axis as well as the protective effects of resveratrol (RSV) and metformin (MET), two potent SIRT1 activators, during the occurrence of "metabolic memory" of cellular senescence (senescent "memory"). Human umbilical vascular endothelial cells (HUVECs) were cultured in either normal glucose (NG)/high glucose (HG) media for 6 days, or 3 days of HG followed by 3 days of NG (HN), with or without RSV or MET treatment. It was shown that HN incubation triggered persistent downregulation of deacetylase SIRT1 and upregulation of acetyltransferase p300, leading to sustained hyperacetylation (at K382) and activation of p53, and subsequent p53/p21-mediated senescent "memory." In contrast, senescent "memory" was abrogated by overexpression of SIRT1 or knockdown of p300. Interestingly, we found that SIRT1 and p300 could regulate each other in response to HN stimulation, suggesting that a delicate balance between acetyltransferases and deacetylases may be particularly important for sustained acetylation and activation of non-histone proteins (such as p53), and eventually the occurrence of "metabolic memory." Furthermore, we found that RSV or MET treatment prevented senescent "memory" by modulating SIRT1/p300/p53/p21 pathway. Notably, early and continuous treatment of MET, but not RSV, was particularly important for preventing senescent "memory." In conclusion, short-term high glucose stimulation could induce sustained endothelial senescence via SIRT1/p300/p53/p21 pathway. RVS or MET treatment could enhance SIRT1-mediated signaling and thus protect against senescent "memory" independent of their glucose lowering mechanisms. Therefore, they may serve as promising therapeutic drugs against the development of "metabolic memory."
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Affiliation(s)
- Erli Zhang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qianyun Guo
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haiyang Gao
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruixia Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Siyong Teng
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongjian Wu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail:
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31
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Wang J, Jiang Z, Lam W, Gullen EA, Yu Z, Wei Y, Wang L, Zeiss C, Beck A, Cheng EC, Wu C, Cheng YC, Zhang Y. Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug. PLoS One 2015; 10:e0140069. [PMID: 26540166 PMCID: PMC4635020 DOI: 10.1371/journal.pone.0140069] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 09/20/2015] [Indexed: 11/25/2022] Open
Abstract
Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.27±0.07μM and 0.18±0.023μM respectively. This inhibition was explicated by Malformin C’s effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug.
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Affiliation(s)
- Jing Wang
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Oncology and Hematology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Zaoli Jiang
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Wing Lam
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Elizabeth A. Gullen
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Zhe Yu
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Ying Wei
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Lihui Wang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Caroline Zeiss
- Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Amanda Beck
- Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Ee-Chun Cheng
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Chunfu Wu
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Yung-Chi Cheng
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail: (YCC); (YZ)
| | - Yixuan Zhang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- * E-mail: (YCC); (YZ)
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Gao G, Chen L, Huang C. Anti-cancer drug discovery: update and comparisons in yeast, Drosophila, and zebrafish. Curr Mol Pharmacol 2015; 7:44-51. [PMID: 24993385 DOI: 10.2174/1874467207666140702113629] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 06/28/2014] [Accepted: 07/02/2014] [Indexed: 12/17/2022]
Abstract
Discovery of novel cancer chemotherapeutics focuses on screening and identifying compounds that can target 'cancer-specific' biological processes while causing minimal toxicity to non-tumor cells. Alternatively, model organisms with highly conserved cancer-related cellular processes relative to human cells may offer new opportunities for anticancer drug discovery when combined with chemical screening. Some organisms used for chemotherapeutic discovery include yeast, Drosophila, and zebrafish which are similar in important ways relevant to cancer study but offer distinct advantages as well. Here, we describe these model attributes and the rationale for using them in cancer drug screening research.
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Affiliation(s)
| | | | - Chuanshu Huang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
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33
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Bakhshaiesh TO, Armat M, Shanehbandi D, Sharifi S, Baradaran B, Hejazi MS, Samadi N. Arsenic Trioxide Promotes Paclitaxel Cytotoxicity in Resistant Breast Cancer Cells. Asian Pac J Cancer Prev 2015. [DOI: 10.7314/apjcp.2015.16.13.5191] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Chakraborty R, Li Y, Zhou L, Golic KG. Corp Regulates P53 in Drosophila melanogaster via a Negative Feedback Loop. PLoS Genet 2015; 11:e1005400. [PMID: 26230084 PMCID: PMC4521751 DOI: 10.1371/journal.pgen.1005400] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 06/26/2015] [Indexed: 01/08/2023] Open
Abstract
The tumor suppressor P53 is a critical mediator of the apoptotic response to DNA double-strand breaks through the transcriptional activation of pro-apoptotic genes. This mechanism is evolutionarily conserved from mammals to lower invertebrates, including Drosophila melanogaster. P53 also transcriptionally induces its primary negative regulator, Mdm2, which has not been found in Drosophila. In this study we identified the Drosophila gene companion of reaper (corp) as a gene whose overexpression promotes survival of cells with DNA damage in the soma but reduces their survival in the germline. These disparate effects are shared by p53 mutants, suggesting that Corp may be a negative regulator of P53. Confirming this supposition, we found that corp negatively regulates P53 protein level. It has been previously shown that P53 transcriptionally activates corp; thus, Corp produces a negative feedback loop on P53. We further found that Drosophila Corp shares a protein motif with vertebrate Mdm2 in a region that mediates the Mdm2:P53 physical interaction. In Corp, this motif mediates physical interaction with Drosophila P53. Our findings implicate Corp as a functional analog of vertebrate Mdm2 in flies.
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Affiliation(s)
- Riddhita Chakraborty
- Department of Biology, University of Utah, Salt Lake City, Utah, United States of America
| | - Ying Li
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Lei Zhou
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Kent G. Golic
- Department of Biology, University of Utah, Salt Lake City, Utah, United States of America
- * E-mail:
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35
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Indo HP, Tomiyoshi T, Suenaga S, Tomita K, Suzuki H, Masuda D, Terada M, Ishioka N, Gusev O, Cornette R, Okuda T, Mukai C, Majima HJ. MnSOD downregulation induced by extremely low 0.1 mGy single and fractionated X-rays and microgravity treatment in human neuroblastoma cell line, NB-1. J Clin Biochem Nutr 2015; 57:98-104. [PMID: 26388666 PMCID: PMC4566025 DOI: 10.3164/jcbn.15-20] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 02/16/2015] [Indexed: 11/22/2022] Open
Abstract
A human neuroblastoma cell line, NB-1, was treated with 24 h of microgravity simulation by clinostat, or irradiated with extremely small X-ray doses of 0.1 or 1.0 mGy using single and 10 times fractionation regimes with 1 and 2 h time-intervals. A quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) examination was performed for apoptosis related factors (BAX, CYTC, APAF1, VDAC1–3, CASP3, CASP8, CASP9 P53, AIF, ANT1 and 2, BCL2, MnSOD, autophagy related BECN and necrosis related CYP-40. The qRT-PCR results revealed that microgravity did not result in significant changes except for a upregulation of proapoptotic VDAC2, and downregulations of proapoptotic CASP9 and antiapoptotic MnSOD. After 0.1 mGy fractionation irradiation, there was increased expression of proapoptotic APAF1 and downregulation of proapoptotic CYTC, VDAC2, VDAC3, CASP8, AIF, ANT1, and ANT2, as well as an increase in expression of antiapoptotic BCL2. There was also a decrease in MnSOD expression with 0.1 mGy fractionation irradiation. These results suggest that microgravity and low-dose radiation may decrease apoptosis but may potentially increase oxidative stress.
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Affiliation(s)
- Hiroko P Indo
- Department of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Tsukasa Tomiyoshi
- Department of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shigeaki Suenaga
- Department of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Kazuo Tomita
- Department of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hiromi Suzuki
- Department of Space Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan ; Life Science Research Group, Department of Science and Applications, Japan Space Forum, 3-2-1 Surugadai, Chiyoda, Tokyo 100-0004, Japan
| | - Daisuke Masuda
- Department of Space Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan ; Utilization & Engineering Department, Japan Manned Space Systems Corporation, 2-1-6 Tsukuba, Ibaraki 305-0047, Japan
| | - Masahiro Terada
- Department of Space Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan ; Space Biosciences Division, NASA Ames Research Center, Moffett Field, California 94035, USA
| | - Noriaki Ishioka
- Department of Space Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan ; Department of Space Biology and Microgravity Sciences, Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, 2-1-1 Sengen, Tsukuba, Ibaraki 305-8505, Japan
| | - Oleg Gusev
- Department of Space Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan ; Department of Space Biology and Microgravity Sciences, Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, 2-1-1 Sengen, Tsukuba, Ibaraki 305-8505, Japan ; Department of Invertebrates Zoology and Functional Morphology, Institute of Fundamental Medicine and Biology, Kazan Federal University 420008, Kremevskaya str., 17 Kazan 420-008, Russia ; Anhydrobiosis Research Unit, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan
| | - Richard Cornette
- Anhydrobiosis Research Unit, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan
| | - Takashi Okuda
- Anhydrobiosis Research Unit, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan
| | - Chiaki Mukai
- Center for Applied Space Medicine and Human Research, Japan Aerospace Exploration Agency, 2-1-1 Sengen, Tsukuba, Ibaraki 305-8505, Japan
| | - Hideyuki J Majima
- Department of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan ; Department of Space Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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Zhang J, Shen L, Sun LQ. The regulation of radiosensitivity by p53 and its acetylation. Cancer Lett 2015; 363:108-18. [DOI: 10.1016/j.canlet.2015.04.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 04/15/2015] [Accepted: 04/15/2015] [Indexed: 12/26/2022]
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Naito A, Yamamoto H, Kagawa Y, Naito Y, Okuzaki D, Otani K, Iwamoto Y, Maeda S, Kikuta J, Nishikawa K, Uemura M, Nishimura J, Hata T, Takemasa I, Mizushima T, Ishii H, Doki Y, Mori M, Ishii M. RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells. J Biol Chem 2015; 290:6326-6337. [PMID: 25605732 PMCID: PMC4358269 DOI: 10.1074/jbc.m114.614859] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 01/09/2015] [Indexed: 01/06/2023] Open
Abstract
Cell cycle-arrested cancer cells are resistant to conventional chemotherapy that acts on the mitotic phases of the cell cycle, although the molecular mechanisms involved in halting cell cycle progression remain unclear. Here, we demonstrated that RFPL4A, an uncharacterized ubiquitin ligase, induced G1 retention and thus conferred decreased sensitivity to chemotherapy in the human colorectal cancer cell line, HCT116. Long term time lapse observations in HCT116 cells bearing a "fluorescence ubiquitin-based cell cycle indicator" identified a characteristic population that is viable but remains in the G1 phase for an extended period of time (up to 56 h). Microarray analyses showed that expression of RFPL4A was significantly up-regulated in these G1-arrested cells, not only in HCT116 cells but also in other cancer cell lines, and overexpression of RFPL4A increased the G1 population and decreased sensitivity to chemotherapy. However, knockdown of RFPL4A expression caused the cells to resume mitosis and induced their susceptibility to anti-cancer drugs in vitro and in vivo. These results indicate that RFPL4A is a novel factor that increases the G1 population and decreases sensitivity to chemotherapy and thus may be a promising therapeutic target for refractory tumor conditions.
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Affiliation(s)
- Atsushi Naito
- From the Departments of Immunology and Cell Biology, Gastroenterological Surgery, and
| | | | - Yoshinori Kagawa
- From the Departments of Immunology and Cell Biology, Gastroenterological Surgery, and the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Yoko Naito
- From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Daisuke Okuzaki
- the DNA-chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, 3-1 Yamada-oka, Osaka University, Suita, Osaka 565-0871, Japan, and
| | | | | | - Sakae Maeda
- From the Departments of Immunology and Cell Biology, Gastroenterological Surgery, and the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Junichi Kikuta
- From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, the Japan Science and Technology Agency (JST), CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan
| | - Keizo Nishikawa
- From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, the Japan Science and Technology Agency (JST), CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan
| | | | | | | | | | | | - Hideshi Ishii
- Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | | | | | - Masaru Ishii
- From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, the Japan Science and Technology Agency (JST), CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan
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38
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Cellular senescence: a hitchhiker’s guide. Hum Cell 2015; 28:51-64. [DOI: 10.1007/s13577-015-0110-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 02/03/2015] [Indexed: 12/21/2022]
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Osman AA, Neskey DM, Katsonis P, Patel AA, Ward AM, Hsu TK, Hicks SC, McDonald TO, Ow TJ, Alves MO, Pickering CR, Skinner HD, Zhao M, Sturgis EM, Kies MS, El-Naggar A, Perrone F, Licitra L, Bossi P, Kimmel M, Frederick MJ, Lichtarge O, Myers JN. Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients. Cancer Res 2015; 75:1205-15. [PMID: 25691460 DOI: 10.1158/0008-5472.can-14-2729] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 01/12/2015] [Indexed: 12/25/2022]
Abstract
TP53 is the most frequently altered gene in head and neck squamous cell carcinoma (HNSCC), with mutations occurring in over two thirds of cases; however, the predictive response of these mutations to cisplatin-based therapy remains elusive. In the current study, we evaluate the ability of the Evolutionary Action score of TP53-coding variants (EAp53) to predict the impact of TP53 mutations on response to chemotherapy. The EAp53 approach clearly identifies a subset of high-risk TP53 mutations associated with decreased sensitivity to cisplatin both in vitro and in vivo in preclinical models of HNSCC. Furthermore, EAp53 can predict response to treatment and, more importantly, a survival benefit for a subset of head and neck cancer patients treated with platinum-based therapy. Prospective evaluation of this novel scoring system should enable more precise treatment selection for patients with HNSCC.
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Affiliation(s)
- Abdullah A Osman
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David M Neskey
- Department of Otolaryngology Head and Neck Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
| | - Panagiotis Katsonis
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Ameeta A Patel
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexandra M Ward
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Teng-Kuei Hsu
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Stephanie C Hicks
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Thomas J Ow
- Department of Otolaryngology Head and Neck Surgery, Albert Einstein School of Medicine, Bronx, New York
| | - Marcus Ortega Alves
- Department of Internal Medicine, Tufts Medical Center, Boston, Massachusetts
| | - Curtis R Pickering
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Heath D Skinner
- Department of Thoracic Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mei Zhao
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eric M Sturgis
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Merrill S Kies
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Adel El-Naggar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Federica Perrone
- Department of Pathology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Lisa Licitra
- Head and Neck Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Paolo Bossi
- Head and Neck Medical Oncology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
| | - Marek Kimmel
- Department of Statistics, Rice University, Houston, Texas
| | - Mitchell J Frederick
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Olivier Lichtarge
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas
| | - Jeffrey N Myers
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jeon BN, Kim MK, Yoon JH, Kim MY, An H, Noh HJ, Choi WI, Koh DI, Hur MW. Two ZNF509 (ZBTB49) isoforms induce cell-cycle arrest by activating transcription of p21/CDKN1A and RB upon exposure to genotoxic stress. Nucleic Acids Res 2014; 42:11447-61. [PMID: 25245946 PMCID: PMC4191422 DOI: 10.1093/nar/gku857] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
ZNF509 is unique among POK family proteins in that four isoforms are generated by alternative splicing. Short ZNF509 (ZNF509S1, -S2 and -S3) isoforms contain one or two out of the seven zinc-fingers contained in long ZNF509 (ZNF509L). Here, we investigated the functions of ZNF509 isoforms in response to DNA damage, showing isoforms to be induced by p53. Intriguingly, to inhibit proliferation of HCT116 and HEK293 cells, we found that ZNF509L activates p21/CDKN1A transcription, while ZNF509S1 induces RB. ZNF509L binds to the p21/CDKN1A promoter either alone or by interacting with MIZ-1 to recruit the co-activator p300 to activate p21/CDKN1A transcription. In contrast, ZNF509S1 binds to the distal RB promoter to interact and interfere with the MIZF repressor, resulting in derepression and transcription of RB. Immunohistochemical analysis revealed that ZNF509 is highly expressed in normal epithelial cells, but was completely repressed in tumor tissues of the colon, lung and skin, indicating a possible role as a tumor suppressor.
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Affiliation(s)
- Bu-Nam Jeon
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Min-Kyeong Kim
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Jae-Hyeon Yoon
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Min-Young Kim
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Haemin An
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Hee-Jin Noh
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Won-Il Choi
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Dong-In Koh
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
| | - Man-Wook Hur
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea
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Chu XT, Cruz JD, Hwang SG, Hong H. Tumorigenic Effects of Endocrine-Disrupting Chemicals are Alleviated by Licorice (Glycyrrhiza glabra) Root Extract through Suppression of AhR Expression in Mammalian Cells. Asian Pac J Cancer Prev 2014. [DOI: 10.7314/apjcp.2014.15.13.5117] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Chu XT, de la Cruz J, Hwang SG, Hong H. Tumorigenic Effects of Endocrine-disrupting Chemicals are Alleviated by Licorice (Glycyrrhiza glabra) Root Extract through Suppression of AhR Expression in Mammalian Cells. Asian Pac J Cancer Prev 2014; 15:4809-13. [DOI: 10.7314/apjcp.2014.15.12.4809] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc Natl Acad Sci U S A 2014; 111:7090-5. [PMID: 24778222 DOI: 10.1073/pnas.1321942111] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the "senescence-messaging secretome" (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho-deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and emphysema. Because plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (SERPIN), is elevated in kl/kl mice and is a critical determinant of replicative senescence in vitro, we hypothesized that a reduction in extracellular proteolytic activity contributes to the accelerated aging-like phenotype of kl/kl mice. Here we show that PAI-1 deficiency retards the development of senescence and protects organ structure and function while prolonging the lifespan of kl/kl mice. These findings indicate that a SERPIN-regulated cell-nonautonomous proteolytic cascade is a critical determinant of senescence in vivo.
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44
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Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer. Expert Rev Mol Med 2013; 15:e12. [PMID: 24074238 DOI: 10.1017/erm.2013.13] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Testicular cancer is the most frequent solid malignant tumour type in men 20-40 years of age. At the time of diagnosis up to 50% of the patients suffer from metastatic disease. In contrast to most other metastatic solid tumours, the majority of metastatic testicular cancer patients can be cured with highly effective cisplatin-based chemotherapy. This review aims to summarise the current knowledge on response to chemotherapy and the biological basis of cisplatin-induced apoptosis in testicular cancer. The frequent presence of wild-type TP53 and the low levels of p53 in complex with the p53 negative feed-back regulator MDM2 contribute to cisplatin sensitivity. Moreover, the high levels of the pluripotency regulator Oct4 and as a consequence of Oct4 expression high levels of miR-17/106b seed family and pro-apoptotic Noxa and the low levels of cytoplasmic p21 (WAF1/Cip1) appear to be causative for the exquisite sensitivity to cisplatin-based therapy of testicular cancer. However, resistance of testicular cancer to cisplatin-based therapy does occur and can be mediated through aberrant levels of the above mentioned key players. Drugs targeting these key players showed, at least pre-clinically, a sensitising effect to cisplatin treatment. Further clinical development of such treatment strategies will lead to new treatment options for platinum-resistant testicular cancers.
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45
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Lee J, Shin YK, Song JY, Lee KW. Protective mechanism of morin against ultraviolet B-induced cellular senescence in human keratinocyte stem cells. Int J Radiat Biol 2013; 90:20-8. [DOI: 10.3109/09553002.2013.835502] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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46
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Cunha D, Cunha R, Côrte-Real M, Chaves SR. Cisplatin-induced cell death in Saccharomyces cerevisiae is programmed and rescued by proteasome inhibition. DNA Repair (Amst) 2013; 12:444-9. [DOI: 10.1016/j.dnarep.2013.02.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/17/2013] [Accepted: 02/17/2013] [Indexed: 11/26/2022]
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Abstract
BACKGROUND The p53 gene is the most frequently mutated gene in cancer and accordingly has been the subject of intensive investigation for almost 30 years. Loss of p53 function due to mutations has been unequivocally demonstrated to promote cancer in both humans and in model systems. As a consequence, there exists an enormous body of information regarding the function of normal p53 in biology and the pathobiological consequences of p53 mutation. It has long been recognised that analysis of p53 has considerable potential as a tool for use in both diagnostic and, to a greater extent, prognostic settings and some significant progress has been made in both of these arenas. OBJECTIVE To provide an overview of the biology of p53, particularly in the context of uses of p53 as a diagnostic tool. METHODS A literature review focused upon the methods and uses of p53 analysis in the diagnosis of sporadic cancers, rare genetic disorders and in detection of residual disease. CONCLUSION p53 is currently an essential diagnostic for the rare inherited cancer prone syndrome (Li-Fraumeni) and is an important diagnostic in only a limited number of settings in sporadic disease. Research in specific cancers indicates that the uses of increasingly well informed p53 mutational analysis are likely to expand to other cancers.
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Affiliation(s)
- Mark T Boyd
- Reader in Molecular Oncology and Director of Laboratories University of Liverpool, p53/MDM2 Research Team, Division of Surgery and Oncology, School of Cancer Studies, 5th Floor, UCD Building, Daulby Street, Liverpool L69 3GA, UK +44 151 706 4185 ; +44 151 706 5826 ;
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DNA damage induced by oridonin involves cell cycle arrest at G2/M phase in human MCF-7 cells. Contemp Oncol (Pozn) 2013; 17:38-44. [PMID: 23788960 PMCID: PMC3685353 DOI: 10.5114/wo.2013.33772] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 07/15/2012] [Accepted: 08/31/2012] [Indexed: 11/17/2022] Open
Abstract
Aim of the study To study the mechanisms of inhibition of cell growth and induction of DNA damage in oridonin-treated MCF-7 human breast cancer cells. Material and methods The cytotoxicity of oridonin-treated MCF-7 cells was measured by MTT assay. Cell cycle phase distribution was analyzed by flow cytometry. P-ATM, P-CHK2, γH2AX and P-P53 protein expressions were detected by Western blot analysis. The expression of r-h2ax and P-ATM was also detected by immunofluorescence staining. The degree of cellular damage of oridonin-induced MCF-7 human breast cancer cells was confirmed by the comet assay analysis of DNA fragmentation. Results Oridonin inhibited cell growth in a time- and dose-dependent manner. The IC50 values at 48 and 72 hours were 78.3 and 31.62 µmol/l, respectively. Oridonin induced G2/M phase arrest in MCF-7 cells. MCF-7 cells treated with oridonin showed significant DNA damage as shown by an increase in olive tail moment (OTM). The protein expression levels of P-ATM, P-CHK2, γH2AX and P-P53 were increased significantly in a dose-dependent manner. Conclusions DNA damage provokes p53-mediated G2/M cell cycle arrest in oridonin-induced MCF-7 cells through the mechanism of CHK2 activation by activated ATM protein kinase, which is induced by oridonin.
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Cao Y, Yang T, Gu C, Yi D. Pigment epithelium-derived factor delays cellular senescence of human mesenchymal stem cells in vitro by reducing oxidative stress. Cell Biol Int 2013; 37:305-13. [PMID: 23359450 DOI: 10.1002/cbin.10041] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Accepted: 12/23/2012] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that represent a promising approach in the field of regenerative medicine; however, this potential diminishes with senescence. Pigment epithelium-derived factor (PEDF) gives some protection by reducing oxidative stress, which is known to accelerate cellular senescence. Thus we hypothesized that PEDF could delay senescence during MSC expansion by reducing oxidative stress. Proliferation and differentiation potentials, oxidative stress, senescence and p53/p16 expressions have been examined. In MSCs cultured under normoxic conditions treated with PEDF, proliferative lifespan in vitro was significantly increased compared with control group not given PEDF, with ∼10 additional population doublings (PD) occurring before terminal growth arrest. Most of the MSCs cultured under normoxic conditions ceased to proliferate after 20-28 PD, while few senescent cells were found in the hypoxic, PEDF-hypoxic and PEDF-normoxic cultures; this was associated with downregulation of p53 and p16 expression and decreased oxidative stress. PEDF also preserved differentiation potentials of MSCs compared with the control group. Thus PEDF suppression of oxidative stress delays cellular senescence and allows greater expansion of MSCs.
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Affiliation(s)
- Yukun Cao
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
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50
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di Pietro A, Koster R, Boersma-van Eck W, Dam WA, Mulder NH, Gietema JA, de Vries EGE, de Jong S. Pro- and anti-apoptotic effects of p53 in cisplatin-treated human testicular cancer are cell context-dependent. Cell Cycle 2012; 11:4552-62. [PMID: 23165211 DOI: 10.4161/cc.22803] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
In murine testicular cancer (TC) cells wild-type p53 contributes to sensitivity to DNA-damaging drugs in a dose-dependent way. In human TC, however, the role of wild-type p53 functionality in chemotherapeutic response remains elusive. We analyzed functionality of wild-type p53 in cisplatin sensitivity in the human TC setting using a p53 short interfering (si)RNA approach. The cisplatin-sensitive TC cell line (Tera), the subline with acquired cisplatin resistance (Tera-CP) and a panel of intrinsically resistant TC cell lines (Scha and 2102EP), all expressing wild-type p53, were used. p53 and p53 transcriptional targets MDM2 and p21 (Waf1/Cip1) (p21) were expressed in a p53 transactivation-dependent way in all TC cell lines. Following cisplatin exposure, expression levels of p53 increased, with a subsequent increase in MDM2 and p21 mRNA and protein levels and Fas cell membrane levels. Downregulation of p53 with siRNA lowered cisplatin-induced apoptosis in Tera and Tera-CP, which was associated with a diminished Fas membrane expression. In contrast, p53 suppression augmented cisplatin-induced apoptosis in Scha and 2102EP and concomitantly strongly suppressed MDM2 and p21 mRNA and protein expression. Our results indicate that p53 is involved in transactivation of pro- and anti-apoptotic genes in untreated and cisplatin-treated TC cells, but subtle differences are present between TC cell lines. The opposite role of p53 in cisplatin-induced apoptosis among TC cell lines demonstrates the importance of the cellular context for the p53 transactivation phenotype in TC cells.
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Affiliation(s)
- Alessandra di Pietro
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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