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Zhang M, Wu B, Gu J. The Pivotal Role of LACTB in the Process of Cancer Development. Int J Mol Sci 2025; 26:1279. [PMID: 39941048 PMCID: PMC11818536 DOI: 10.3390/ijms26031279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
The mitochondrial serine β-lactamase-like protein LACTB has emerged as a critical regulator in cancer biology, distinguished by its unique structural and functional attributes. Defined by its conserved penicillin-binding proteins and β-lactamases (PBP-βLs) domain and SXXK catalytic motif, LACTB demonstrates properties distinct from its prokaryotic homologs, including the ability to polymerize into filaments. These structural characteristics enable LACTB to modulate mitochondrial organization and enzymatic activity, influencing lipid metabolism and indirectly affecting cellular proliferation. Importantly, the expression and functional roles of LACTB exhibit cancer-type-specific variation, underscoring its dual function as both a tumor suppressor and an oncogene. Decreased LACTB expression is associated with poor clinical outcomes in cancers such as breast cancer, lung cancer, and colorectal cancer, while specific mutations and regulatory mechanisms have been linked to its oncogenic activity in osteosarcoma and pancreatic adenocarcinoma. Mechanistically, LACTB regulates key processes in cancer progression, including mitochondrial dynamics, epithelial-mesenchymal transition (EMT), and cell death pathways. This duality highlights LACTB as a promising therapeutic target and underscores its relevance in advancing precision oncology strategies. This review provides a comprehensive analysis of expression level, structure-function relationships, and the diverse roles of LACTB in oncogenesis, underscoring its promise as a focal point for precision cancer therapies.
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Affiliation(s)
- Minghui Zhang
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; (M.Z.); (B.W.)
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China
| | - Bowen Wu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; (M.Z.); (B.W.)
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China
| | - Jinke Gu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; (M.Z.); (B.W.)
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2
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Abdalla M, Abdelkhalig SM, Edet UO, Zothantluanga JH, Umoh EA, Moglad E, Nkang NA, Hader MM, Alanazi TMR, AlShouli S, Al-Shouli S. Molecular dynamics-based computational investigations on the influence of tumor suppressor p53 binding protein against other proteins/peptides. Sci Rep 2024; 14:29871. [PMID: 39622863 PMCID: PMC11612205 DOI: 10.1038/s41598-024-81499-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 11/27/2024] [Indexed: 12/06/2024] Open
Abstract
The tumor-suppressing p-53 binding protein is a crucial protein that is involved in the prevention of cancer via its regulatory effect on a number of cellular processes. Recent evidence indicates that it interacts with a number of other proteins involved in cancer in ways that are not fully understood. An understanding of such interactions could provide insights into novel ways p53 further exerts its tumour prevention role via its interactions with diverse proteins. Thus, this study aimed to examine the interactions of the p53 protein with other proteins (peptides and histones) using molecular simulation dynamics. We opted for a total of seven proteins, namely 2LVM, 2MWO, 2MWP, 4CRI, 4 × 34, 5Z78, and 6MYO (control), and had their PBD files retrieved from the protein database. These proteins were then docked against the p-53 protein and the resulting interactions were examined using molecular docking simulations run at 500 ns. The result of the interactions revealed the utilisation of various amino acids in the process. The peptide that interacted with the highest number of amino acids was 5Z78 and these were Lys10, Gly21, Trp24, Pro105, His106, and Arg107, indicating a stronger interaction. The RMSD and RMSF values indicate that the complexes formed were stable, with 4CRI, 6MYO, and 2G3R giving the most stable values (less than 2.5 Å). Other parameters, including the SASA, Rg, and number of hydrogen bonds, all indicated the formation of fairly stable complexes. Our study indicates that overall, the interactions of 53BP1 with p53K370me2, p53K382me2, methylated K810 Rb, p53K381acK382me2, and tudor-interacting repair regulator protein indicated interactions that were not as strong as those with the histone protein. Thus, it could be that P53 may mediate its tumour suppressing effect via interactions with amino acids and histone.
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Affiliation(s)
- Mohnad Abdalla
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, China.
| | - Sozan M Abdelkhalig
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia
| | - Uwem O Edet
- Department of Biological (Microbiology), Faculty of Natural and Applied Sciences, Arthur Jarvis University, Akpabuyo, Cross River State, Nigeria.
| | - James H Zothantluanga
- Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, 786004, Assam, India
| | - Ekementeabasi Aniebo Umoh
- Department of Human Physiology, Faculty of Basic Medical Sciences, Arthur Jarvis University, Akpabuyo, Cross River State, Nigeria
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, P.O. Box 173, Alkharj, 11942, Saudi Arabia
| | - Nkoyo Ani Nkang
- Science Laboratory Department, Faculty of Biological Sciences, University of Calabar, Calabar, Cross River State, Nigeria
| | - Meshari M Hader
- Dietary Department, Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia
| | | | - Sawsan AlShouli
- Pharmacy Department, Security Forces Hospital, Riyadh, 11481, Saudi Arabia
| | - Samia Al-Shouli
- Immunology Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, 11461, Saudi Arabia
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Lu D, Faizi M, Drown B, Simerzin A, François J, Bradshaw G, Kelleher N, Jambhekar A, Gunawardena J, Lahav G. Temporal regulation of gene expression through integration of p53 dynamics and modifications. SCIENCE ADVANCES 2024; 10:eadp2229. [PMID: 39454005 PMCID: PMC11506164 DOI: 10.1126/sciadv.adp2229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 09/20/2024] [Indexed: 10/27/2024]
Abstract
The master regulator of the DNA damage response, the transcription factor p53, orchestrates multiple downstream responses and coordinates repair processes. In response to double-strand DNA breaks, p53 exhibits pulses of expression, but how it achieves temporal coordination of downstream responses remains unclear. Here, we show that p53's posttranslational modification state is altered between its first and second pulses of expression. We show that acetylations at two sites, K373 and K382, were reduced in the second pulse, and these acetylations differentially affected p53 target genes, resulting in changes in gene expression programs over time. This interplay between dynamics and modification may offer a strategy for cellular hubs like p53 to temporally organize multiple processes in individual cells.
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Affiliation(s)
- Dan Lu
- Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Marjan Faizi
- Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Bryon Drown
- Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
| | - Alina Simerzin
- Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Joshua François
- Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Gary Bradshaw
- Laboratory of Systems Pharmacology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Neil Kelleher
- Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
| | - Ashwini Jambhekar
- Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
- Ludwig Center at Harvard Medical School, Boston, MA 02115, USA
| | - Jeremy Gunawardena
- Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Galit Lahav
- Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
- Ludwig Center at Harvard Medical School, Boston, MA 02115, USA
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Jana S, Mondal M, Mahale S, Gupta B, Prasasvi KR, Kandasami L, Jha N, Chowdhury A, Santosh V, Kanduri C, Somasundaram K. PITAR, a DNA damage-inducible cancer/testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA. eLife 2024; 12:RP88256. [PMID: 39302097 PMCID: PMC11415074 DOI: 10.7554/elife.88256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024] Open
Abstract
In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 Associated RNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.
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Affiliation(s)
- Samarjit Jana
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
| | - Mainak Mondal
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
| | - Sagar Mahale
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of GothenburgGothenburgSweden
| | - Bhavana Gupta
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
| | - Kaval Reddy Prasasvi
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
| | - Lekha Kandasami
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
| | - Neha Jha
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
| | - Abhishek Chowdhury
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
| | - Vani Santosh
- Department of Neuropathology, National Institute of Mental Health and NeurosciencesBangaloreIndia
| | - Chandrasekhar Kanduri
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of GothenburgGothenburgSweden
| | - Kumaravel Somasundaram
- Department of Microbiology and Cell Biology, Indian Institute of Science BangaloreBangaloreIndia
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Yin Q, Hu Y, Dong Z, Lu J, Wang H. Cellular, Structural Basis, and Recent Progress for Targeting Murine Double Minute X (MDMX) in Tumors. J Med Chem 2024; 67:14723-14741. [PMID: 39185935 DOI: 10.1021/acs.jmedchem.4c00913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Murine double minute X (MDMX) is an oncoprotein that mainly has a negative regulatory effect on the tumor suppressor p53 to induce tumorigenesis. As MDMX is highly expressed in various types of tumor cells, targeting and inhibiting MDMX are becoming a promising strategy for treating cancers. However, the high degree of structural homology between MDMX and its homologous protein murine double minute 2 (MDM2) is a great challenge for the development of MDMX-targeted therapies. This review introduces the structure, distribution, and regulation of the MDMX, summarizes the structural features and structure-activity relationships (SARs) of MDMX ligands, and focuses on the differences between MDMX and MDM2 in these aspects. Our purpose of this work is to propose potential strategies to achieve the specific targeting of MDMX.
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Affiliation(s)
- Qikun Yin
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Yuemiao Hu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Zhiwen Dong
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Jing Lu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
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Patel H, Sheikh MS, Huang Y. ECRG2/SPINK7 Tumor Suppressor as Modulator of DNA Damage Response. Int J Mol Sci 2024; 25:5854. [PMID: 38892042 PMCID: PMC11172197 DOI: 10.3390/ijms25115854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics.
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Affiliation(s)
| | - M. Saeed Sheikh
- Department of Pharmacology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA;
| | - Ying Huang
- Department of Pharmacology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA;
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Zhang W, Vaubel RA, Oh JH, Mladek AC, Talele S, Zhang W, Waller KL, Burgenske DM, Sarkaria JN, Elmquist WF. Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma. Mol Cancer Ther 2024; 23:47-55. [PMID: 37828724 PMCID: PMC10843165 DOI: 10.1158/1535-7163.mct-23-0217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/03/2023] [Accepted: 10/10/2023] [Indexed: 10/14/2023]
Abstract
MDM2-p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified "Delivery - Potency - Efficacy" relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2-p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine "active" unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2-p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood-brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly "poor" BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.
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Affiliation(s)
- Wenjuan Zhang
- Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | | | - Ju-Hee Oh
- Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Ann C. Mladek
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Surabhi Talele
- Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Wenqiu Zhang
- Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Katie L. Waller
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | | | - Jann N. Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - William F. Elmquist
- Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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Ma DD, Shi WJ, Li SY, Zhang JG, Lu ZJ, Long XB, Liu X, Huang CS, Ying GG. Ephedrine and cocaine cause developmental neurotoxicity and abnormal behavior in zebrafish. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2023; 265:106765. [PMID: 37979497 DOI: 10.1016/j.aquatox.2023.106765] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/20/2023]
Abstract
Ephedrine (EPH) and cocaine (COC) are illegal stimulant drugs, and have been frequently detected in aquatic environments. EPH and COC have negative effects on the nervous system and cause abnormal behaviors in mammals and fish at high concentrations, but their mechanisms of neurotoxicity remain unclear in larvae fish at low concentrations. To address this issue, zebrafish embryos were exposed to EPH and COC for 14 days post-fertilization (dpf) at 10, 100, and 1000 ng L-1. The bioaccumulation, development, behavior, cell neurotransmitter levels and apoptosis were detected to investigate the developmental neurotoxicity (DNT) of EPH and COC. The results showed that EPH decreased heart rate, while COC increased heart rate. EPH caused cell apoptosis in the brain by AO staining. In addition, behavior analysis indicated that EPH and COC affected spontaneous movement, touch-response, swimming activity and anxiety-like behaviors. EPH and COC altered the levels of the neurotransmitters dopamine (DA) and γ-aminobutyric acid (GABA) with changes of the transcription of genes related to the DA and GABA pathways. These findings indicated that EPH and COC had noticeable DNT in the early stage of zebrafish at environmentally relevant concentrations.
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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; 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.
| | - 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
| | - 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
| | - 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
| | - 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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Venkatachalapathy H, Yang Z, Azarin SM, Sarkar CA, Batchelor E. Pulsed stimuli entrain p53 to synchronize single cells and modulate cell-fate determination. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.24.563786. [PMID: 37961090 PMCID: PMC10634792 DOI: 10.1101/2023.10.24.563786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Entrainment to an external stimulus enables a synchronized oscillatory response across a population of cells, increasing coherent responses by reducing cell-to-cell heterogeneity. It is unclear whether the property of entrainability extends to systems where responses are intrinsic to the individual cell, rather than dependent on coherence across a population of cells. Using a combination of mathematical modeling, time-lapse fluorescence microscopy, and single-cell tracking, we demonstrated that p53 oscillations triggered by DNA double-strand breaks (DSBs) can be entrained with a periodic damage stimulus, despite such synchrony not known to function in effective DNA damage responses. Surprisingly, p53 oscillations were experimentally entrained over a wider range of DSB frequencies than predicted by an established computational model for the system. We determined that recapitulating the increased range of entrainment frequencies required, non-intuitively, a less robust oscillator and wider steady-state valley on the energy landscape. Further, we show that p53 entrainment can lead to altered expression dynamics of downstream targets responsible for cell fate in a manner dependent on target mRNA stability. Overall, this study demonstrates that entrainment can occur in a biological oscillator despite the apparent lack of an evolutionary advantage conferred through synchronized responses and highlights the potential of externally entraining p53 dynamics to reduce cellular variability and synchronize cell-fate responses for therapeutic outcomes.
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Wu Y, Sun Y, Xu B, Yang M, Wang X, Zhao X. SCARNA10 regulates p53 acetylation-dependent transcriptional activity. Biochem Biophys Res Commun 2023; 669:38-45. [PMID: 37262951 DOI: 10.1016/j.bbrc.2023.05.091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/03/2023]
Abstract
The tumor suppressor p53 is involved in variety of cell progresses including cell cycle arrest, apoptosis, DNA repair, senescence, cell metabolism and ferroptosis. Here, we identified lncRNA SCARNA10 (Small Cajal Body-Specific RNA 10) as a novel cellular factor that interacts with the DNA binding domain (DBD) of p53. Upon binding the DBD of p53 and CREB-binding protein (CBP), SCARNA10 promotes the acetylation of p53, and activates p53-mediated transcriptional activation. Overexpress or knockdown SCARNA10 leads to up (or down)-regulation of p53-mediated transcriptional activation, whereas not affecting p53 protein levels. Moreover, SCARNA10 directly activates transcription by increasing the acetylation of p53 C-terminal domain (CTD) without affecting p53 phosphorylation at Ser15. These results indicate that SCARNA10 is a novel factor which regulates p53 acetylation-dependent transcriptional activity and tumor suppression.
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Affiliation(s)
- Yanxia Wu
- Molecular Cancer Research Center, Seventh Affiliated Hospital, School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China
| | - Yanxi Sun
- Molecular Cancer Research Center, Seventh Affiliated Hospital, School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China
| | - Binchu Xu
- Molecular Cancer Research Center, Seventh Affiliated Hospital, School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China
| | - Mo Yang
- Molecular Cancer Research Center, Seventh Affiliated Hospital, School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China
| | - Xingwu Wang
- Molecular Cancer Research Center, Seventh Affiliated Hospital, School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China.
| | - Xiaocheng Zhao
- Molecular Cancer Research Center, Seventh Affiliated Hospital, School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China.
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11
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Li WF, Alfason L, Huang C, Tang Y, Qiu L, Miyagishi M, Wu SR, Kasim V. p52-ZER6: a determinant of tumor cell sensitivity to MDM2-p53 binding inhibitors. Acta Pharmacol Sin 2023; 44:647-660. [PMID: 35995868 PMCID: PMC9958181 DOI: 10.1038/s41401-022-00973-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/28/2022] [Indexed: 11/08/2022]
Abstract
Targeting MDM2-p53 interaction has emerged as a promising antitumor therapeutic strategy. Several MDM2-p53 inhibitors have advanced into clinical trials, but results are not favorable. The lack of appropriate biomarkers for selecting patients has been assumed as the critical reason for this failure. We previously identified ZER6 isoform p52-ZER6 as an oncogene upregulated in tumor tissues. In this study we investigated whether p52-ZER6 acted as a blocker of MDM2-p53 binding inhibitors, and whether p52-ZER6 could be used as a biomarker of MDM2-p53 binding inhibitors. In p53 wild-type colorectal carcinoma HCT116, hepatocarcinoma HepG2 and breast cancer MCF-7 cells, overexpression of p52-ZER6 enhanced MDM2-p53 binding and promoted p53 ubiquitination/proteasomal degradation. Furthermore, overexpression of p52-ZER6 in the tumor cells dose-dependently reduced their sensitivity to both nutlin and non-nutlin class MDM2-p53 binding inhibitors. We showed that p52-ZER6 restored tumor cell viability, which was suppressed by nutlin-3, through restoring their proliferation potential while suppressing their apoptotic rate, suggesting that MDM2-p53 binding inhibitors might not be effective for patients with high p52-ZER6 levels. We found that nutlin-3 treatment or p52-ZER6 knockdown alone promoted the accumulation of p53 protein in the tumor cells, and their combinatorial treatment significantly increased the accumulation of p53 protein. In HCT116 cell xenograft nude mouse model, administration of shp52-ZER6 combined with an MDM2-p53 binding inhibitor nutlin-3 exerted synergistic antitumor response. In conclusion, this study reveals that p52-ZER6 might be a potential biomarker for determining patients appropriate for MDM2-p53 binding inhibition-based antitumor therapy, and demonstrates the potential of combinatorial therapy using MDM2-p53 binding inhibitors and p52-ZER6 inhibition.
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Affiliation(s)
- Wen-Fang Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Leader Alfason
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Can Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
| | - Yu Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Li Qiu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Makoto Miyagishi
- Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, 305-8566, Japan
| | - Shou-Rong Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China.
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China.
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12
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Arif W, Mathur B, Saikali MF, Chembazhi UV, Toohill K, Song YJ, Hao Q, Karimi S, Blue SM, Yee BA, Van Nostrand EL, Bangru S, Guzman G, Yeo GW, Prasanth KV, Anakk S, Cummins CL, Kalsotra A. Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death. Nat Commun 2023; 14:551. [PMID: 36759613 PMCID: PMC9911759 DOI: 10.1038/s41467-023-35932-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/09/2023] [Indexed: 02/11/2023] Open
Abstract
Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis, illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how the accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver damage.
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Affiliation(s)
- Waqar Arif
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA
- College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Bhoomika Mathur
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Michael F Saikali
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
| | - Ullas V Chembazhi
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Katelyn Toohill
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - You Jin Song
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Qinyu Hao
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Saman Karimi
- Department of Pathology, College of Medicine, Cancer Center, University of Illinois Hospital and Health Science Chicago, Chicago, IL, USA
| | - Steven M Blue
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Brian A Yee
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Eric L Van Nostrand
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Sushant Bangru
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Cancer Center @ Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Grace Guzman
- Department of Pathology, College of Medicine, Cancer Center, University of Illinois Hospital and Health Science Chicago, Chicago, IL, USA
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Kannanganattu V Prasanth
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Cancer Center @ Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Cancer Center @ Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Carolyn L Cummins
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
| | - Auinash Kalsotra
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Cancer Center @ Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Carl R. Woese Institute of Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
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13
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Yu Z, Su Y, Lu Y, Yang Y, Wang F, Zhang S, Chang Y, Wong KC, Li X. Topological identification and interpretation for single-cell gene regulation elucidation across multiple platforms using scMGCA. Nat Commun 2023; 14:400. [PMID: 36697410 PMCID: PMC9877026 DOI: 10.1038/s41467-023-36134-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 01/16/2023] [Indexed: 01/26/2023] Open
Abstract
Single-cell RNA sequencing provides high-throughput gene expression information to explore cellular heterogeneity at the individual cell level. A major challenge in characterizing high-throughput gene expression data arises from challenges related to dimensionality, and the prevalence of dropout events. To address these concerns, we develop a deep graph learning method, scMGCA, for single-cell data analysis. scMGCA is based on a graph-embedding autoencoder that simultaneously learns cell-cell topology representation and cluster assignments. We show that scMGCA is accurate and effective for cell segregation and batch effect correction, outperforming other state-of-the-art models across multiple platforms. In addition, we perform genomic interpretation on the key compressed transcriptomic space of the graph-embedding autoencoder to demonstrate the underlying gene regulation mechanism. We demonstrate that in a pancreatic ductal adenocarcinoma dataset, scMGCA successfully provides annotations on the specific cell types and reveals differential gene expression levels across multiple tumor-associated and cell signalling pathways.
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Affiliation(s)
- Zhuohan Yu
- School of Artificial Intelligence, Jilin University, Jilin, China
| | - Yanchi Su
- School of Artificial Intelligence, Jilin University, Jilin, China
| | - Yifu Lu
- School of Artificial Intelligence, Jilin University, Jilin, China
| | - Yuning Yang
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Fuzhou Wang
- Department of Computer Science, City University of Hong Kong, Hong Kong SAR, China
| | - Shixiong Zhang
- Department of Computer Science, City University of Hong Kong, Hong Kong SAR, China
| | - Yi Chang
- School of Artificial Intelligence, Jilin University, Jilin, China
| | - Ka-Chun Wong
- Department of Computer Science, City University of Hong Kong, Hong Kong SAR, China.
| | - Xiangtao Li
- School of Artificial Intelligence, Jilin University, Jilin, China.
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14
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Alhaddad L, Chuprov-Netochin R, Pustovalova M, Osipov AN, Leonov S. Polyploid/Multinucleated Giant and Slow-Cycling Cancer Cell Enrichment in Response to X-ray Irradiation of Human Glioblastoma Multiforme Cells Differing in Radioresistance and TP53/PTEN Status. Int J Mol Sci 2023; 24:ijms24021228. [PMID: 36674747 PMCID: PMC9865596 DOI: 10.3390/ijms24021228] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/27/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Radioresistance compromises the efficacy of radiotherapy for glioblastoma multiforme (GBM), the most devastating and common brain tumor. The present study investigated the relationship between radiation tolerance and formation of polyploid/multinucleated giant (PGCC/MGCC) and quiescent/senescent slow-cycling cancer cells in human U-87, LN-229, and U-251 cell lines differing in TP53/PTEN status and radioresistance. We found significant enrichment in MGCC populations of U-87 and LN-229 cell lines, and generation of numerous small mononuclear (called Raju cells, or RJ cells) U-87-derived cells that eventually form cell colonies, in a process termed neosis, in response to X-ray irradiation (IR) at single acute therapeutic doses of 2-6 Gy. For the first time, single-cell high-content imaging and analysis of Ki-67- and EdU-coupled fluorescence demonstrated that the IR exposure dose-dependently augments two distinct GBM cell populations. Bifurcation of Ki-67 staining suggests fast-cycling and slow-cycling populations with a normal-sized nuclear area, and with an enlarged nuclear area, including one resembling the size of PGCC/MGCCs, that likely underlie the highest radioresistance and propensity for repopulation of U-87 cells. Proliferative activity and anchorage-independent survival of GBM cell lines seem to be related to neosis, low level of apoptosis, fraction of prematurely stress-induced senescent MGCCs, and the expression of p63 and p73, members of p53 family transcription factors, but not to the mutant p53. Collectively, our data support the importance of the TP53wt/PTENmut genotype for the maintenance of cycling radioresistant U-87 cells to produce a significant amount of senescent MGCCs as an IR stress-induced adaptation response to therapeutic irradiation doses.
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Affiliation(s)
- Lina Alhaddad
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia
| | - Roman Chuprov-Netochin
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia
| | - Margarita Pustovalova
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia
- State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), 123098 Moscow, Russia
| | - Andreyan N. Osipov
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia
- State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), 123098 Moscow, Russia
- N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russia
- Correspondence:
| | - Sergey Leonov
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia
- Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia
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15
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Context-Dependent Function of Long Noncoding RNA PURPL in Transcriptome Regulation during p53 Activation. Mol Cell Biol 2022; 42:e0028922. [PMID: 36342127 PMCID: PMC9753727 DOI: 10.1128/mcb.00289-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
PURPL is a p53-induced lncRNA that suppresses basal p53 levels. Here, we investigated PURPL upon p53 activation in liver cancer cells, where it is expressed at significantly higher levels than other cell types. Using isoform sequencing, we discovered novel PURPL transcripts that have a retained intron and/or previously unannotated exons. To determine PURPL function upon p53 activation, we performed transcriptome sequencing (RNA-Seq) after depleting PURPL using CRISPR interference (CRISPRi), followed by Nutlin treatment to induce p53. Strikingly, although loss of PURPL in untreated cells altered the expression of only 7 genes, loss of PURPL resulted in altered expression of ~800 genes upon p53 activation, revealing a context-dependent function of PURPL. Pathway analysis suggested that PURPL is important for fine-tuning the expression of specific genes required for mitosis. Consistent with these results, we observed a significant decrease in the percentage of mitotic cells upon PURPL depletion. Collectively, these data identify novel transcripts from the PURPL locus and suggest that PURPL delicately moderates the expression of mitotic genes in the context of p53 activation to control cell cycle arrest.
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16
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Anticancer Therapeutic Strategies Targeting p53 Aggregation. Int J Mol Sci 2022; 23:ijms231911023. [PMID: 36232329 PMCID: PMC9569952 DOI: 10.3390/ijms231911023] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/10/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
p53 is a tumor suppressor protein that is mutated in more than 50% of cancer cases. When mutated, it frequently results in p53 oncogenic gain of function (GOF), resulting in a greater tendency to aggregate in the phase separation and phase transition pathway. GOFs related to p53 aggregation include chemoresistance, which makes therapy even more difficult. The therapies available for the treatment of cancer are still quite limited, so the study of new molecules and therapeutic targets focusing on p53 aggregates is a promising strategy against cancer. In this review, we classify anticancer molecules with antiaggregation properties into four categories: thiol alkylating agents, designed peptides, agents with chaperone-based mechanisms that inhibit p53 aggregation, and miscellaneous compounds with anti-protein aggregation properties that have been studied in neurodegenerative diseases. Furthermore, we highlight autophagy as a possible degradation pathway for aggregated p53. Here, considering cancer as a protein aggregation disease, we review strategies that have been used to disrupt p53 aggregates, leading to cancer regression.
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Chen Z, Cui L, Xu L, Liu Z, Liang Y, Li X, Zhang Y, Li Y, Liu S, Li H. Characterization of chicken p53 transcriptional function via parallel genome-wide chromatin occupancy and gene expression analysis. Poult Sci 2022; 101:102164. [PMID: 36167023 PMCID: PMC9513273 DOI: 10.1016/j.psj.2022.102164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 07/14/2022] [Accepted: 08/24/2022] [Indexed: 11/21/2022] Open
Abstract
The tumor suppressor p53, which acts primarily as a transcription factor, can regulate infections from various viruses in chickens. However, the underlying mechanisms of the antiviral functions of chicken p53 (chp53) remain unclear due to the lack of detailed information on its transcriptional regulation. Here, to gain comprehensive insights into chp53 transcriptional regulatory function in a global and unbiased manner, we determined the genome-wide chromatin occupancy of chp53 by chromatin immunoprecipitation, which was followed by sequencing and chp53-mediated gene expression profile by RNA sequencing using chemically immortalized leghorn male hepatoma (LMH) cells with ectopic expression of chp53 as the model. The integrated parallel genome-wide chromatin occupancy and gene expression analysis characterized chp53 chromatin occupancy and identified 754 direct target genes of chp53. Furthermore, functional annotation and cross-species comparative biological analyses revealed the conserved key biological functions and DNA binding motifs of p53 between chickens and humans, which may be due to the consensus amino acid sequence and structure of p53 DNA-binding domains. The present study, to our knowledge, provides the first comprehensive characterization of the chp53 transcriptional regulatory network, and can possibly help to improve our understanding of p53 transcriptional regulatory mechanisms and their antiviral functions in chickens.
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Funasaki S, Mehanna S, Ma W, Nishizawa H, Kamikubo Y, Sugiyama H, Ikeda S, Motoshima T, Hasumi H, Linehan WM, Schmidt LS, Ricketts C, Suda T, Oike Y, Kamba T, Baba M. Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate. Cancer Sci 2022; 113:2352-2367. [PMID: 35396773 PMCID: PMC9277412 DOI: 10.1111/cas.15364] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 03/26/2022] [Accepted: 04/02/2022] [Indexed: 11/29/2022] Open
Abstract
Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.
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Affiliation(s)
- Shintaro Funasaki
- Laboratory of Cancer MetabolismInternational Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Sally Mehanna
- Laboratory of Cancer MetabolismInternational Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Wenjuan Ma
- Laboratory of Cancer MetabolismInternational Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Hidekazu Nishizawa
- Laboratory of Cancer MetabolismInternational Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Department of UrologyGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yasuhiko Kamikubo
- Department of Human Health ScienceGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Hiroshi Sugiyama
- Department of ChemistryGraduate School of ScienceKyoto UniversityKyotoJapan
| | - Shuji Ikeda
- Department of ChemistryGraduate School of ScienceKyoto UniversityKyotoJapan
| | - Takanobu Motoshima
- Department of UrologyGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Hisashi Hasumi
- Department of UrologyGraduate School of MedicineYokohama City UniversityYokohamaJapan
| | - W. Marston Linehan
- Urologic Oncology BranchNational Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Laura S. Schmidt
- Urologic Oncology BranchNational Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
- Basic Science ProgramFrederick National Laboratory for Cancer ResearchNational Cancer InstituteFrederickMarylandUSA
| | - Chris Ricketts
- Urologic Oncology BranchNational Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Toshio Suda
- Laboratory of Stem Cell RegulationInternational Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
- Cancer Science Institute of SingaporeCentre for Translational MedicineNational University of SingaporeSingapore CitySingapore
| | - Yuichi Oike
- Department of Molecular GeneticsGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Tomomi Kamba
- Department of UrologyGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Masaya Baba
- Laboratory of Cancer MetabolismInternational Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
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da Mota VHS, Freire de Melo F, de Brito BB, Silva FAFD, Teixeira KN. Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development. World J Clin Oncol 2022; 13:496-504. [PMID: 35949428 PMCID: PMC9244969 DOI: 10.5306/wjco.v13.i6.496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/16/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It is known that p53 suppression is an important marker of poor prognosis of cancers, especially in solid tumors of the breast, lung, stomach, and esophagus; liposarcomas, glioblastomas, and leukemias. Because p53 has mouse double minute 2 (MDM2) as its primary negative regulator, this molecular docking study seeks to answer the following hypotheses: Is the interaction between DS-3032B and MDM2 stable enough for this drug to be considered as a promising neoplastic inhibitor? AIM To analyze, in silico, the chemical bonds between the antagonist DS-3032B and its binding site in MDM2. METHODS For molecular docking simulations, the file containing structures of MDM2 (receptor) and the drug DS-3032B (ligand) were selected. The three-dimensional structure of MDM2 was obtained from Protein Data Bank, and the one for DS-3032B was obtained from PubChem database. The location and dimensions of the Grid box was determined using AutoDock Tools software. In this case, the dimensions of the Grid encompassed the entire receptor. The ligand DS-3032B interacts with the MDM2 receptor in a physiological environment with pH 7.4; thus, to simulate more reliably, its interaction was made with the calculation for the prediction of its protonation state using the MarvinSketch® software. Both ligands, with and without the protonation, were prepared for molecular docking using the AutoDock Tools software. This software detects the torsion points of the drug and calculates the angle of the torsions. Molecular docking simulations were performed using the tools of the AutoDock platform connected to the Vina software. The analyses of the amino acid residues involved in the interactions between the receptor and the ligand as well as the twists of the ligand, atoms involved in the interactions, and type, strength, and length of the interactions were performed using the PyMol software (pymol.org/2) and Discovery Studio from BIOVIA®. RESULTS The global alignment indicated crystal structure 5SWK was more suitable for docking simulations by presenting the p53 binding site. The three-dimensional structure 5SWK for MDM2 was selected from Protein Data Bank and the three-dimensional structure of DS-3032B was selected from PubChem (Compound CID: 73297272; Milademetan). After molecular docking simulations, the most stable conformer was selected for both protonated and non-protonated DS-3032B. The interaction between MDM2 and DS-3032B occurs with high affinity; no significant difference was observed in the affinity energies between the MDM2/pronated DS-3032B (-9.9 kcal/mol) and MDM2/non-protonated DS-3032B conformers (-10.0 kcal/mol). Sixteen amino acid residues of MDM2 are involved in chemical bonds with the protonated DS-3032B; these 16 residues of MDM2 belong to the p53 biding site region and provide high affinity to interaction and stability to drug-protein complex. CONCLUSION Molecular docking indicated that DS-3032B antagonist binds to the same region of the p53 binding site in the MDM2 with high affinity and stability, and this suggests therapeutic efficiency.
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Affiliation(s)
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Kuo HC, Luo L, Ma Y, Williams NT, da Silva Campos L, Attardi LD, Lee CL, Kirsch DG. The p53 Transactivation Domain 1-Dependent Response to Acute DNA Damage in Endothelial Cells Protects against Radiation-Induced Cardiac Injury. Radiat Res 2022; 198:145-153. [PMID: 35512345 PMCID: PMC9397489 DOI: 10.1667/rade-22-00001.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/04/2022] [Indexed: 11/03/2022]
Abstract
Thoracic radiation therapy can cause endothelial injury in the heart, leading to cardiac dysfunction and heart failure. Although it has been demonstrated that the tumor suppressor p53 functions in endothelial cells to prevent the development of radiation-induced myocardial injury, the key mechanism(s) by which p53 regulates the radiosensitivity of cardiac endothelial cells is not completely understood. Here, we utilized genetically engineered mice that express mutations in p53 transactivation domain 1 (TAD1) (p5325,26) or mutations in p53 TAD1 and TAD2 (p5325,26,53,54) specifically in endothelial cells to study the p53 transcriptional program that protects cardiac endothelial cells from ionizing radiation in vivo. p5325,26,53,54 loses the ability to drive transactivation of p53 target genes after irradiation while p5325,26 can induce transcription of a group of non-canonical p53 target genes, but not the majority of classic radiation-induced p53 targets critical for p53-mediated cell cycle arrest and apoptosis. After 12 Gy whole-heart irradiation, we found that both p5325,26 and p5325,26,53,54 sensitized mice to radiation-induced cardiac injury, in contrast to wild-type p53. Histopathological examination suggested that mutation of TAD1 contributes to myocardial necrosis after whole-heart irradiation, while mutation of both TAD1 and TAD2 abolishes the ability of p53 to prevent radiation-induced heart disease. Taken together, our results show that the transcriptional program downstream of p53 TAD1, which activates the acute DNA damage response after irradiation, is necessary to protect cardiac endothelial cells from radiation injury in vivo.
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Affiliation(s)
- Hsuan-Cheng Kuo
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710
| | - Lixia Luo
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710
| | - Yan Ma
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710
| | - Nerissa T Williams
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710
| | | | - Laura D Attardi
- Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305.,Department of Genetics, Stanford University School of Medicine, Stanford, California 94305
| | - Chang-Lung Lee
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710.,Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710
| | - David G Kirsch
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.,Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710
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21
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Novel CDK9 inhibitor oroxylin A promotes wild-type P53 stability and prevents hepatocellular carcinoma progression by disrupting both MDM2 and SIRT1 signaling. Acta Pharmacol Sin 2022; 43:1033-1045. [PMID: 34188177 DOI: 10.1038/s41401-021-00708-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/28/2021] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal tumours worldwide. However, the effects of first-line sorafenib treatment in advanced HCC fail to prolong patients' survival due to the highly heterogeneous characteristics of HCC etiology. Cyclin-dependent kinase 9 (CDK9) is an important target in the continuous development of cancer therapy. Here, we demonstrate that CDK9 is closely associated with the progression of HCC and can serve as an HCC therapeutic target by modulating the recovery of wild-type p53 (wt-p53) function. We prove that mouse double minute 2 homologue (MDM2) and Sirtuin 1 (SIRT1) are phosphorylated by CDK9 at Ser166 and Ser47, respectively. Inhibition of CDK9 not only reduces the MDM2-mediated ubiquitination and degradation of wt-p53 but also increases wt-p53 stability by suppressing deacetylase activity of SIRT1. Thus, inhibition of CDK9 promotes the wt-p53 stabilization and prevents HCC progression. However, excessive inhibition by high concentrations of specific CDK9 inhibitors counteracts the promotion of p53 stability and reduces their anti-HCC activity because of extreme general transcription repression. The effects of a novel CDK9 inhibitor named oroxylin A (OA) from Scutellaria baicalensis are explored, with the results indicating that OA shows moderate and controlled inhibition of CDK9 activity and expression, and stabilizes wt-p53 by inhibiting CDK9-regulated MDM2 and SIRT1 signaling. These outcomes indicate the high therapeutic potential of OA against HCC and its low toxicity in normal tissue. This study demonstrates a novel mechanism for the regulation of wt-p53 by CDK9 and indicates that OA is a potential candidate for HCC therapy.
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22
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Synergistic Effect of Erastin Combined with Nutlin-3 on Vestibular Schwannoma Cells as p53 Modulates Erastin-Induced Ferroptosis Response. JOURNAL OF ONCOLOGY 2022; 2022:7507857. [PMID: 35359340 PMCID: PMC8961447 DOI: 10.1155/2022/7507857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 12/18/2022]
Abstract
Vestibular schwannoma (VS) is a rare neurotology neoplasm that results in partial neurological defects. As we know, a comprehensive understanding of basic mechanisms and targeted therapy is vital for disease management. In VS, p53 has been proved to suppress tumor progression via a cooperative with the key protein, merlin, as well as regulation of the cell cycle. However, there are more potential mechanisms of p53 in VS needed to exploit. First, via genome-wide RNA expression analysis, we identified differentially expressed genes in VS compared with normal nerves, and then, bioinformatics analyses were used to analyze these differential expression data and suggested a high level of enrichment of cysteine and glutathione metabolism pathways in VS. Meanwhile, we observed a downregulation of SLC7A11/xCT, a component of the cystine/glutamate antiporter (also known as system xc−) involved in cystine uptake. Next, for a deeper study, our group extracted tumor cells from vestibular schwannoma tissues and established two immortalized cell lines named JEI-001 and JEI-002. Secondly, in our established cells, we demonstrated that ferroptosis participated in erastin-induced growth inhibition. As a novel cell death process, ferroptosis driven by iron-mediated lipid reactive oxygen species (lipid ROS), as well as cysteine and glutathione metabolism. Furthermore, ferroptosis contributes to the inhibitory effects of tumor suppressor p53. Here, we show that p53 sensitizes schwannoma cells to ferroptosis by repressing expression of SLC7A11/xCT. Finally, erastin combined with Nutlin-3, which s to p53 activation, triggered antitumor effects of ferroptosis on the growth of schwannoma cells in vitro. These findings present potential mechanism of p53 in schwannomas and raise the possibility of treatment strategies directed against this pathogenesis.
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23
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Jiménez A, Lu D, Kalocsay M, Berberich MJ, Balbi P, Jambhekar A, Lahav G. Time‐series transcriptomics and proteomics reveal alternative modes to decode p53 oscillations. Mol Syst Biol 2022; 18:e10588. [PMID: 35285572 PMCID: PMC8919251 DOI: 10.15252/msb.202110588] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 02/16/2022] [Accepted: 02/19/2022] [Indexed: 12/21/2022] Open
Affiliation(s)
- Alba Jiménez
- Department of Systems Biology Blavatnik Institute at Harvard Medical School Boston MA USA
| | - Dan Lu
- Department of Systems Biology Blavatnik Institute at Harvard Medical School Boston MA USA
| | - Marian Kalocsay
- Department of Systems Biology Blavatnik Institute at Harvard Medical School Boston MA USA
- Laboratory of Systems Pharmacology Blavatnik Institute at Harvard Medical School Boston MA USA
| | - Matthew J Berberich
- Laboratory of Systems Pharmacology Blavatnik Institute at Harvard Medical School Boston MA USA
- Center for Protein Degradation Dana‐Farber Cancer Institute Boston MA USA
| | - Petra Balbi
- Department of Systems Biology Blavatnik Institute at Harvard Medical School Boston MA USA
| | - Ashwini Jambhekar
- Department of Systems Biology Blavatnik Institute at Harvard Medical School Boston MA USA
- Ludwig Center at Harvard Medical School Boston MA USA
| | - Galit Lahav
- Department of Systems Biology Blavatnik Institute at Harvard Medical School Boston MA USA
- Ludwig Center at Harvard Medical School Boston MA USA
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24
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Zhang Z, Bao Z, Gao P, Yao J, Wang P, Chai D. Diverse Roles of F-BoxProtein3 in Regulation of Various Cellular Functions. Front Cell Dev Biol 2022; 9:802204. [PMID: 35127719 PMCID: PMC8807484 DOI: 10.3389/fcell.2021.802204] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/23/2021] [Indexed: 01/06/2023] Open
Abstract
Accumulated evidence shows that the F-box protein 3 (FBXO3) has multiple biological functions, including regulation of immune pathologies, neuropathic diseases and antiviral response. In this review article, we focus on the role of FBXO3 in inflammatory disorders and human malignancies. We also describe the substrates of FBXO3, which contribute to inflammatory disorders and cancers. We highlight that the high expression of FBXO3 is frequently observed in rheumatoid arthritis, leukemia, pituitary adenoma, and oral squamous cell carcinoma. Moreover, we discuss the regulation of FBXO3 by both carcinogens and cancer preventive agents. Our review provides a comprehensive understanding of the role of FBXO3 in various biological systems and elucidates how FBXO3 regulates substrate ubiquitination and degradation during various physiological and pathological processes. Therefore, FBXO3 can be a novel target in the treatment of human diseases including carcinomas.
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Affiliation(s)
- Zhiyang Zhang
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Zhengqi Bao
- Department of Orthopedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Penglian Gao
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Junyi Yao
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Peter Wang
- Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical College, Bengbu, China
- *Correspondence: Peter Wang, ; Damin Chai,
| | - Damin Chai
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- *Correspondence: Peter Wang, ; Damin Chai,
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25
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Potential Effects of Metformin on the Vitality, Invasion, and Migration of Human Vascular Smooth Muscle Cells via Downregulating lncRNA-ATB. DISEASE MARKERS 2022; 2022:7480199. [PMID: 35027983 PMCID: PMC8752240 DOI: 10.1155/2022/7480199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 12/16/2022]
Abstract
Objective To elucidate the role of metformin in influencing VSMCs via the involvement of lncRNA-ATB. Methods qRT-PCR was conducted to detect serum levels of lncRNA-ATB and p53 in CHD patients (n = 50) and healthy subjects (n = 50). Correlation in serum levels of lncRNA-ATB and p53 in CHD patients was assessed by Pearson correlation test. ROC curves were depicted for analyzing the predictive potential of lncRNA-ATB in the occurrence of CHD. After metformin induction in VSMCs overexpressing lncRNA-ATB, relative levels of lncRNA-ATB and p53 were detected. Meanwhile, proliferative, migratory, and invasive abilities in VSMCs were, respectively, examined by CCK-8 and transwell assay. The interaction between lncRNA-ATB and p53 was tested by RIP. In addition, the coregulation of lncRNA-ATB and p53 in cell functions of VSMCs was finally determined. Results Increased serum level of lncRNA-ATB and decreased p53 level were detected in CHD patients than those of healthy subjects. LncRNA-ATB could interact with p53 and negatively regulate its level. In addition, lncRNA-ATB could serve as a potential biomarker for predicting the occurrence of CHD. The overexpression of lncRNA-ATB triggered viability, migratory, and invasive abilities in VSMCs, and the above trends were abolished by metformin induction. The overexpression of p53 partially abolished the promotive effects of lncRNA-ATB on proliferative, migratory, and invasive abilities in VSMCs. Conclusions Metformin induction inhibits proliferative, migratory, and invasive abilities in VSMCs by downregulating lncRNA-ATB, which may be related to p53 activation.
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26
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Yang X, Wang X, Li Z, Duan S, Li H, Jin J, Zhang Z, Gu W. An unexpected role for Dicer as a reader of the unacetylated DNA binding domain of p53 in transcriptional regulation. SCIENCE ADVANCES 2021; 7:eabi6684. [PMID: 34705508 PMCID: PMC8550248 DOI: 10.1126/sciadv.abi6684] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 09/04/2021] [Indexed: 06/02/2023]
Abstract
Here, we identified Dicer as a major cellular factor that recognizes the DNA binding domain (DBD) of p53 in a manner dependent on its acetylation status. Upon binding the unacetylated DBD, Dicer is recruited to the promoters of p53 target genes, where it represses p53-mediated transcriptional activation. Conversely, knockdown or knockout of endogenous Dicer leads to up-regulation of p53-mediated transcriptional activation without increasing its protein levels. Moreover, Dicer-mediated repression is independent of its intrinsic endoribonuclease activity; instead, Dicer directly represses transcription by recruiting the SUV39H1 histone methyltransferase. However, upon DNA damage, Dicer-mediated repression is abrogated by stress-induced acetylation at the DBD of p53. Notably, the inability of acetylation-defective p53-3KR in transcription is partially but significantly restored upon loss of Dicer expression. Our study reveals that Dicer acts as an unexpected acetylation “reader” for p53 and thus has important implications regarding the mechanism of acetylation-mediated regulation of p53 transcriptional program.
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Affiliation(s)
- Xin Yang
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
| | - Xingwu Wang
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
| | - Zhiming Li
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
| | - Shoufu Duan
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
| | - Huan Li
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Zhiguo Zhang
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
- Department of Pediatrics and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
| | - Wei Gu
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave., New York, NY 10032, USA
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27
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Mullard M, Lavaud M, Regnier L, Tesfaye R, Ory B, Rédini F, Verrecchia F. Ubiquitin-specific proteases as therapeutic targets in paediatric primary bone tumours? Biochem Pharmacol 2021; 194:114797. [PMID: 34678225 DOI: 10.1016/j.bcp.2021.114797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 01/04/2023]
Abstract
In children and young adults, primary malignant bone tumours are mainly composed of osteosarcoma and Ewing's sarcoma. Despite advances in treatments, nearly 40% of patients succumb to these diseases. In particular, the clinical outcome of metastatic osteosarcoma or Ewing's sarcoma remains poor, with less than 30% of patients who develop metastases surviving five years after initial diagnosis. Over the last decade, the cancer research community has shown considerable interest in the processes of protein ubiquitination and deubiquitination. In particular, a growing number of studies show the relevance to target the ubiquitin-specific protease (USP) family in various cancers. This review provides an update on the current knowledge regarding the implication of these USPs in the progression of bone sarcoma: osteosarcoma and Ewing's sarcoma.
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Affiliation(s)
- Mathilde Mullard
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Mélanie Lavaud
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Laura Regnier
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Robel Tesfaye
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Benjamin Ory
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Françoise Rédini
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France
| | - Franck Verrecchia
- INSERM, Université de Nantes, UMR1238, "Bone Sarcoma and Remodelling of Calcified Tissues", 44000 Nantes, France.
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28
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Differential Transcriptional Regulation of Polymorphic p53 Codon 72 in Metabolic Pathways. Int J Mol Sci 2021; 22:ijms221910793. [PMID: 34639134 PMCID: PMC8509680 DOI: 10.3390/ijms221910793] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/01/2021] [Accepted: 10/01/2021] [Indexed: 11/16/2022] Open
Abstract
p53 is a transcription factor that is activated under DNA damage stress and regulates the expression of proapoptotic genes including the expression of growth arrest genes to subsequently determine the fate of cells. To investigate the functional differences of polymorphic p53 codon 72, we constructed isogenic lines encoding each polymorphic p53 codon 72 based on induced pluripotent stem cells, which can endogenously express each polymorphic p53 protein only, encoding either the arginine 72 (R72) variant or proline 72 (P72) variant, respectively. We found that there was no significant functional difference between P72 and R72 cells in growth arrest or apoptosis as a representative function of p53. In the comprehensive analysis, the expression pattern of the common p53 target genes, including cell cycle arrest or apoptosis, was also increased regardless of the polymorphic p53 codon 72 status, whereas the expression pattern involved in metabolism was decreased and more significant in R72 than in P72 cells. This study noted that polymorphic p53 codon 72 differentially regulated the functional categories of metabolism and not the pathways that determine cell fate, such as growth arrest and apoptosis in cells exposed to genotoxic stress.
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29
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Vadivel Gnanasundram S, Bonczek O, Wang L, Chen S, Fahraeus R. p53 mRNA Metabolism Links with the DNA Damage Response. Genes (Basel) 2021; 12:1446. [PMID: 34573428 PMCID: PMC8465283 DOI: 10.3390/genes12091446] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/14/2022] Open
Abstract
Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which mainly involves cell cycle regulation and DNA repair processes. The tumor suppressor p53 plays a pivotal role in the DDR by halting the cell cycle and facilitating the DNA repair processes. Various pathways and factors participating in the detection and repair of DNA have been described, including scores of RNA-binding proteins (RBPs) and RNAs. It has become increasingly clear that p53's role is multitasking, and p53 mRNA regulation plays a prominent part in the DDR. This review is aimed at covering the p53 RNA metabolism linked to the DDR and highlights the recent findings.
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Affiliation(s)
| | - Ondrej Bonczek
- Department of Medical Biosciences, Umeå University, 901-87 Umeå, Sweden; (O.B.); (L.W.); (S.C.)
- RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656-53 Brno, Czech Republic
| | - Lixiao Wang
- Department of Medical Biosciences, Umeå University, 901-87 Umeå, Sweden; (O.B.); (L.W.); (S.C.)
| | - Sa Chen
- Department of Medical Biosciences, Umeå University, 901-87 Umeå, Sweden; (O.B.); (L.W.); (S.C.)
| | - Robin Fahraeus
- Department of Medical Biosciences, Umeå University, 901-87 Umeå, Sweden; (O.B.); (L.W.); (S.C.)
- RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656-53 Brno, Czech Republic
- Inserm UMRS1131, Institut de Genetique Moleculaire, Universite Paris 7, Hopital St Louis, F-75010 Paris, France
- International Centre for Cancer Vaccine Science, University of Gdansk, 80-822 Gdansk, Poland
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30
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Wang K, Du H, Zhuang Q, Lu H, Xu R, Xue D. Cyclin-dependent kinase 1 shows to be a potential genetic target for chemical cystitis. Immun Inflamm Dis 2021; 9:950-958. [PMID: 34080795 PMCID: PMC8342199 DOI: 10.1002/iid3.454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/23/2021] [Accepted: 04/29/2021] [Indexed: 01/26/2023] Open
Abstract
Background In the present study, we aimed to explore whether common genetic targets or signaling pathways existed in chemical cystitis. Methods Gene Expression Omnibus (GEO) database was used to search the related gene expression profiles. The differentially expressed genes (DEGs) were identified by using GEO2R. The DAVID 6.8 Beta and R software were used to perform Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology function analysis of DEGs. The protein‐protein interaction network was constructed by STRING 11.0 to reveal the potential gene interactions. The expression of cyclin‐dependent kinase 1 (Cdk1) at the messnger RNA (mRNA) and protein levels was examined by real‐time polymerase chain reaction (PCR) and Western blot analysis analysis, respectively. Results The GEO database was searched, and the gene expression profiles of GSE55986 and GSE68539 were downloaded. A total of 262 DEGs and 356 DEGs were identified from GSE55986 and GSE68539, respectively. We found that the p53 signaling pathway might play a key role in the development of chemical cystitis, and Cdk1 acted as a crucial gene in the p53 signaling pathway. Moreover, the experimental results of real‐time PCR and Western blot analysis analysis demonstrated that the expression of Cdk1 at the mRNA and protein levels in cystitis tissues was significantly increased in different animal models of chemical cystitis compared with the control group. Conclusion Cdk1 might be a potential pathogenic genetic target for chemical cystitis.
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Affiliation(s)
- Kun Wang
- Department of Surgical Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Huaping Du
- Department of Neurology, Suzhou Ninth People's Hospital, Suzhou, Jiangsu, China
| | - Qianfeng Zhuang
- Department of Surgical Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Hao Lu
- Department of Surgical Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Renfang Xu
- Department of Surgical Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Dong Xue
- Department of Surgical Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
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31
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Nguyen D, Yang K, Chiao L, Deng Y, Zhou X, Zhang Z, Zeng SX, Lu H. Inhibition of tumor suppressor p73 by nerve growth factor receptor via chaperone-mediated autophagy. J Mol Cell Biol 2021; 12:700-712. [PMID: 32285119 PMCID: PMC7749740 DOI: 10.1093/jmcb/mjaa017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/06/2019] [Accepted: 01/13/2020] [Indexed: 01/08/2023] Open
Abstract
The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis. Here, we identify nerve growth factor receptor (NGFR, p75NTR, or CD271) as a novel negative p73 regulator. p73 activates NGFR transcription, which, in turn, promotes p73 degradation in a negative feedback loop. NGFR directly binds to p73 central DNA-binding domain and suppresses p73 transcriptional activity as well as p73-mediated apoptosis in cancer cells. Surprisingly, we uncover a previously unknown mechanism of NGFR-facilitated p73 degradation through the chaperone-mediated autophagy (CMA) pathway. Collectively, our studies demonstrate a new oncogenic function for NGFR in inactivating p73 activity by promoting its degradation through the CMA.
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Affiliation(s)
- Daniel Nguyen
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Kun Yang
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Lucia Chiao
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.,Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yun Deng
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.,Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Xiang Zhou
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.,Institute of Biomedical Sciences, Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Zhen Zhang
- Department of Radiation Oncology, Shanghai Cancer Center, Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
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32
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Mutated p53 in HGSC-From a Common Mutation to a Target for Therapy. Cancers (Basel) 2021; 13:cancers13143465. [PMID: 34298679 PMCID: PMC8304959 DOI: 10.3390/cancers13143465] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Ovarian high-grade serous cancer (HGSC), the most common and the deadliest subtype of epithelial ovarian cancer, is characterized by frequent mutations in the TP53 tumor suppressor gene, encoding for the p53 protein in nearly 100% of cases. This makes p53 the focus of many studies trying to understand its role in HGSC. The aim of our review paper is to provide updates on the latest findings related to the role of mutant p53 in HGSC. This includes the clinical outcomes of TP53 mutations in HGSC, upstream regulators and downstream effectors of p53, its function in the earliest stages of HGSC development and in the interplay between the tumor cells and their microenvironment. We summarize with the likelihood of p53 mutants to serve as biomarkers for early diagnosis and as targets for therapy in HGSC. Abstract Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.
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Beck J, Turnquist C, Horikawa I, Harris C. Targeting cellular senescence in cancer and aging: roles of p53 and its isoforms. Carcinogenesis 2021; 41:1017-1029. [PMID: 32619002 DOI: 10.1093/carcin/bgaa071] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/26/2020] [Accepted: 06/29/2020] [Indexed: 12/11/2022] Open
Abstract
Cellular senescence and the associated secretory phenotype (SASP) promote disease in the aged population. Targeting senescent cells by means of removal, modulation of SASP or through cellular reprogramming represents a novel therapeutic avenue for treating cancer- and age-related diseases such as neurodegeneration, pulmonary fibrosis and renal disease. Cellular senescence is partly regulated by the TP53 gene, a critical tumor suppressor gene which encodes 12 or more p53 protein isoforms. This review marks a significant milestone of 40 years of Carcinogenesis publication history and p53 research and 15 years of p53 isoform research. The p53 isoforms are produced through initiation at alternative transcriptional and translational start sites and alternative mRNA splicing. These truncated p53 isoform proteins are endogenously expressed in normal human cells and maintain important functional roles, including modulation of full-length p53-mediated cellular senescence, apoptosis and DNA repair. In this review, we discuss the mechanisms and functions of cellular senescence and SASP in health and disease, the regulation of cellular senescence by p53 isoforms, and the therapeutic potential of targeting cellular senescence to treat cancer- and age-associated diseases.
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Affiliation(s)
- Jessica Beck
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.,Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
| | - Casmir Turnquist
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.,University of Oxford Medical School, John Radcliffe Hospital, Oxford, UK
| | - Izumi Horikawa
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Curtis Harris
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Ding W. The Ongoing Unmet Needs in Chronic Lymphocytic Leukemia: TP53 Disruption, Richter, and Beyond. Hematol Oncol Clin North Am 2021; 35:739-759. [PMID: 34174984 DOI: 10.1016/j.hoc.2021.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Despite recent success in regard to targeted therapies in chronic lymphocytic leukemia (CLL), patients with TP53 disruption (including deletion and/or mutation) continue to have poor outcomes compared with other patients with CLL. In this article, a review of common TP53 mutations in CLL, and recent trials using novel targeted agents in CLL patients with TP53 disruption, is provided with the goal of emphasizing the need to continuously focus on this area of research. In addition, limited but available data on double refractory CLL to BTK inhibitor and BCL-2 inhibitor, and on Richter syndrome, are reviewed.
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Affiliation(s)
- Wei Ding
- Division of Hematology, Mayo Clinic, 200 First Street, Southwest, Rochester, MN 55905, USA.
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Liu K, Wang Y, Li H. The Role of Ninjurin1 and Its Impact beyond the Nervous System. Dev Neurosci 2021; 42:159-169. [PMID: 33657559 DOI: 10.1159/000512222] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/09/2020] [Indexed: 11/19/2022] Open
Abstract
Ninjurin1 (Ninj1) is a double-transmembrane cell surface protein that could promote nerve regeneration in the process of the peripheral nervous system injury and repairment. Nonetheless, the accurate function of Ninj1 in the central nervous system and outside the nervous system is not completely clear. According to the recent studies, we found that Ninj1 is also aberrantly expressed in various pathophysiological processes in vivo, including inflammation, tumorigenesis, and vascular, bone, and muscle homeostasis. These findings suggest that Ninj1 may play an influential role during these pathophysiological processes. Our review summarizes the diverse roles of Ninj1 in multiple pathophysiological processes inside and outside the nervous system. Ninj1 should be considered as an important and novel therapeutic target in certain diseases, such as inflammatory diseases and ischemic diseases. Our study provided a better understanding of Ninj1 in different pathophysiological processes and thereby provided the theoretical support for further research.
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Affiliation(s)
- Ke Liu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongge Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,
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Abstract
The DEAD-box helicase family member DDX3X (DBX, DDX3) functions in nearly all stages of RNA metabolism and participates in the progression of many diseases, including virus infection, inflammation, intellectual disabilities and cancer. Over two decades, many studies have gradually unveiled the role of DDX3X in tumorigenesis and tumour progression. In fact, DDX3X possesses numerous functions in cancer biology and is closely related to many well-known molecules. In this review, we describe the function of DDX3X in RNA metabolism, cellular stress response, innate immune response, metabolic stress response in pancreatic β cells and embryo development. Then, we focused on the role of DDX3X in cancer biology and systematically demonstrated its functions in various aspects of tumorigenesis and development. To provide a more intuitive understanding of the role of DDX3X in cancer, we summarized its functions and specific mechanisms in various types of cancer and presented its involvement in cancer-related signalling pathways.
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Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation. Sci Rep 2021; 11:4480. [PMID: 33627789 PMCID: PMC7904805 DOI: 10.1038/s41598-021-83979-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 02/10/2021] [Indexed: 12/20/2022] Open
Abstract
The prevalence and dire implications of mutations in the tumour suppressor, p53, highlight its appeal as a chemotherapeutic target. We recently showed that impairing cellular antioxidant systems via inhibition of SLC7A11, a component of the system xc- cystine-glutamate antiporter, enhances sensitivity to mutant-p53 targeted therapy, APR-246. We investigated whether this synergy extends to other genes, such as those encoding enzymes of the pentose phosphate pathway (PPP). TKT, one of the major enzymes of the PPP, is allegedly regulated by NRF2, which is in turn impaired by accumulated mutant-p53 protein. Therefore, we investigated the relationship between mutant-p53, TKT and sensitivity to APR-246. We found that mutant-p53 does not alter expression of TKT, nor is TKT modulated directly by NRF2, suggesting a more complex mechanism at play. Furthermore, we found that in p53null cells, knockdown of TKT increased sensitivity to APR-246, whilst TKT overexpression conferred resistance to the drug. However, neither permutation elicited any effect on cells overexpressing mutant-p53 protein, despite mediating oxidative stress levels in a similar fashion to that in p53-null cells. In sum, this study has unveiled TKT expression as a determinant for sensitivity to APR-246 in p53-null cells.
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Zhou X, Zou L, Chen W, Yang T, Luo J, Wu K, Shu F, Tan X, Yang Y, Cen S, Li C, Mao X. Flubendazole, FDA-approved anthelmintic, elicits valid antitumor effects by targeting P53 and promoting ferroptosis in castration-resistant prostate cancer. Pharmacol Res 2021; 164:105305. [PMID: 33197601 DOI: 10.1016/j.phrs.2020.105305] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/20/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023]
Abstract
On account of incurable castration-resistant prostate cancer (CRPC) inevitably developing after treating with androgen deprivation therapy, it is an urgent need to find new therapeutic strategies. Flubendazole is a well-known anti-malarial drug that is recently reported to be a potential anti-tumor agent in various types of human cancer cells. However, whether flubendazole could inhibit the castration-resistant prostate cancer has not been well charified. Thus, the aim of the present study was to characterize the precise mechanism of action of flubendazole on the CRPC. In this study, we investigated the potential effect of flubendazole on cell proliferation, cell cycle and cell death in CRPC cells (PC3 and DU145). We found that flubendazole inhibited cell proliferation, caused cell cycle arrest in G2/M phase and promoted cell death in vitro, and suppressed growth of CRPC tumor in xenograft models. In addition, we reported that flubendazole induced the expression of P53, which partly accounted for the G2/M phase arrest and led to inhibition of the transcription of SLC7A11, and then downregulated the GPX4, which is a major ferroptosis-related gene. Furthermore, flubendazole exhibited synergistic effect with 5-fluorouracil (5-Fu) in chemotherapy of CRPC. This study provides biological evidence that flubendazole is a novel P53 inducer which exerts anti-proliferation and pro-apoptosis effects in CRPC through hindering the cell cycle and activating the ferroptosis, and indicates that a novel utilization of flubendazole in neoadjuvant chemotherapy of CRPC.
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Affiliation(s)
- Xumin Zhou
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China; Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Libin Zou
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Wenbin Chen
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Taowei Yang
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Junqi Luo
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Kaihui Wu
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Fangpeng Shu
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, PR China
| | - Xiao Tan
- Department of Urology, The First Affiliated Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Yu Yang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen 518036, PR China
| | - Shengren Cen
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Chuanyin Li
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China.
| | - Xiangming Mao
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China.
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Isoform-Specific Roles of Mutant p63 in Human Diseases. Cancers (Basel) 2021; 13:cancers13030536. [PMID: 33572532 PMCID: PMC7866788 DOI: 10.3390/cancers13030536] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary The protein p63 belongs to the family of the p53 tumor suppressor. Mouse models have, however, shown that it is not a classical tumor suppressor but instead involved in developmental processes. Mutations in the p63 gene cause several developmental defects in human patients characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia due to p63’s role as a master regulator of epidermal development. In addition, p63 plays a key role as a quality control factor in oocytes and p63 mutations can result either in compromised genetic quality control or premature cell death of all oocytes. Abstract The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility.
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Voss L, Guttek K, Reddig A, Reinhold A, Voss M, Schraven B, Reinhold D. Screening of FDA-Approved Drug Library Identifies Adefovir Dipivoxil as Highly Potent Inhibitor of T Cell Proliferation. Front Immunol 2021; 11:616570. [PMID: 33488629 PMCID: PMC7821167 DOI: 10.3389/fimmu.2020.616570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 11/25/2020] [Indexed: 12/30/2022] Open
Abstract
Repositioning of approved drugs for identifying new therapeutic purposes is an alternative, time and cost saving strategy to classical drug development. Here, we screened a library of 786 FDA-approved drugs to find compounds, which can potentially be repurposed for treatment of T cell-mediated autoimmune diseases. Investigating the effect of these diverse substances on mitogen-stimulated proliferation of both, freshly stimulated and pre-activated (48 h) peripheral blood mononuclear cells (PBMCs), we discovered Adefovir Dipivoxil (ADV) as very potent compound, which inhibits T cell proliferation in a nanomolar range. We further analyzed the influence of ADV on proliferation, activation, cytokine production, viability and apoptosis of freshly stimulated as well as pre-activated human T cells stimulated with anti-CD3/CD28 antibodies. We observed that ADV was capable of suppressing the proliferation in both T cell stimulation systems in a dose-dependent manner (50% inhibition [IC50]: 63.12 and 364.8 nM for freshly stimulated T cells and pre-activated T cells, respectively). Moreover, the drug impaired T cell activation and inhibited Th1 (IFN-γ), Th2 (IL-5), and Th17 (IL-17) cytokine production dose-dependently. Furthermore, ADV treatment induced DNA double-strand breaks (γH2AX foci expression), which led to an increase of p53-phospho-Ser15 expression. In response to DNA damage p21 and PUMA are transactivated by p53. Subsequently, this caused cell cycle arrest at G0/G1 phase and activation of the intrinsic apoptosis pathway. Our results indicate that ADV could be a new potential candidate for treatment of T cell-mediated autoimmune diseases. Prospective studies should be performed to verify this possible therapeutic application of ADV for such disorders.
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Affiliation(s)
- Linda Voss
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Karina Guttek
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Annika Reddig
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Annegret Reinhold
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infection and Inflammation (GC-I3), Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Martin Voss
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Burkhart Schraven
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infection and Inflammation (GC-I3), Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Dirk Reinhold
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infection and Inflammation (GC-I3), Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
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Barros EP, Demir Ö, Soto J, Cocco MJ, Amaro RE. Markov state models and NMR uncover an overlooked allosteric loop in p53. Chem Sci 2020; 12:1891-1900. [PMID: 34163952 PMCID: PMC8179107 DOI: 10.1039/d0sc05053a] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The tumor suppressor p53 is the most frequently mutated gene in human cancer, and thus reactivation of mutated p53 is a promising avenue for cancer therapy. Analysis of wildtype p53 and the Y220C cancer mutant long-timescale molecular dynamics simulations with Markov state models and validation by NMR relaxation studies has uncovered the involvement of loop L6 in the slowest motions of the protein. Due to its distant location from the DNA-binding surface, the conformational dynamics of this loop has so far remained largely unexplored. We observe mutation-induced stabilization of alternate L6 conformations, distinct from all experimentally-determined structures, in which the loop is both extended and located further away from the DNA-interacting surface. Additionally, the effect of the L6-adjacent Y220C mutation on the conformational landscape of the functionally-important loop L1 suggests an allosteric role to this dynamic loop and the inactivation mechanism of the mutation. Finally, the simulations reveal a novel Y220C cryptic pocket that can be targeted for p53 rescue efforts. Our approach exemplifies the power of the MSM methodology for uncovering intrinsic dynamic and kinetic differences among distinct protein ensembles, such as for the investigation of mutation effects on protein function. Wildtype and Y220C L1 and L6 loops conformational landscape, with MSM-identified L6 states highlighted on the right.![]()
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Affiliation(s)
- Emilia P Barros
- Department of Chemistry and Biochemistry, University of California San Diego La Jolla CA 92093 USA +1-858-534-9645 +1-858-534-9629
| | - Özlem Demir
- Department of Chemistry and Biochemistry, University of California San Diego La Jolla CA 92093 USA +1-858-534-9645 +1-858-534-9629
| | - Jenaro Soto
- Department of Pharmaceutical Sciences, University of California Irvine Irvine CA 92697 USA
| | - Melanie J Cocco
- Department of Pharmaceutical Sciences, University of California Irvine Irvine CA 92697 USA.,Department of Molecular Biology and Biochemistry, University of California Irvine Irvine 92697 CA USA
| | - Rommie E Amaro
- Department of Chemistry and Biochemistry, University of California San Diego La Jolla CA 92093 USA +1-858-534-9645 +1-858-534-9629
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Nameki R, Chang H, Reddy J, Corona RI, Lawrenson K. Transcription factors in epithelial ovarian cancer: histotype-specific drivers and novel therapeutic targets. Pharmacol Ther 2020; 220:107722. [PMID: 33137377 DOI: 10.1016/j.pharmthera.2020.107722] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023]
Abstract
Transcription factors (TFs) are major contributors to cancer risk and somatic development. In preclinical and clinical studies, direct or indirect inhibition of TF-mediated oncogenic gene expression profiles have proven to be effective in many tumor types, highlighting this group of proteins as valuable therapeutic targets. In spite of this, our understanding of TFs in epithelial ovarian cancer (EOC) is relatively limited. EOC is a heterogeneous disease composed of five major histologic subtypes; high-grade serous, low-grade serous, endometrioid, clear cell and mucinous. Each histology is associated with unique clinical etiologies, sensitivity to therapies, and molecular signatures - including diverse transcriptional regulatory programs. While some TFs are shared across EOC subtypes, a set of TFs are expressed in a histotype-specific manner and likely explain part of the histologic diversity of EOC subtypes. Targeting TFs present with unique opportunities for development of novel precision medicine strategies for ovarian cancer. This article reviews the critical TFs in EOC subtypes and highlights the potential of exploiting TFs as biomarkers and therapeutic targets.
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Affiliation(s)
- Robbin Nameki
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Heidi Chang
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jessica Reddy
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Rosario I Corona
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kate Lawrenson
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Chen HY, Lin CH, Teng SC. Stress-induced p53 drives BAG5 cochaperone expression to control α-synuclein aggregation in Parkinson's disease. Aging (Albany NY) 2020; 12:20702-20727. [PMID: 33085644 PMCID: PMC7655153 DOI: 10.18632/aging.103998] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/01/2020] [Indexed: 12/13/2022]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder with the pathological hallmark of α-synuclein aggregation. Dysregulation of α-synuclein homeostasis caused by aging, genetic, and environmental factors underlies the pathogenesis of PD. While chaperones are essential for proteostasis, whether modulation of cochaperones may participate in PD formation has not been fully characterized. Here, we assessed the expression of several HSP70- and HSP90-related factors under various stresses and found that BAG5 expression is distinctively elevated in etoposide- or H2O2-treated SH-SY5Y cells. Stress-induced p53 binds to the BAG5 promoter directly to stimulate BAG5. Induced BAG5 binds α-synuclein and HSP70 in both cell cultures and brain lysates from PD patients. Overexpressed BAG5 may result in the loss of its ability to promote HSP70. Importantly, α-synuclein aggregation in SH-SY5Y cells requires BAG5. BAG5 expression is also detected in transgenic SNCA mutant mice and in PD patients. Together, our data reveal stress-induced p53-BAG5-HSP70 regulation that provides a potential therapeutic angle for PD.
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Affiliation(s)
- Huan-Yun Chen
- Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shu-Chun Teng
- Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Center of Precision Medicine, National Taiwan University, Taipei, Taiwan
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Mechanism of PRL2 phosphatase-mediated PTEN degradation and tumorigenesis. Proc Natl Acad Sci U S A 2020; 117:20538-20548. [PMID: 32788364 DOI: 10.1073/pnas.2002964117] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies.
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Guo L, Kang JS, Kang NJ, Choi YW. S-petasin induces apoptosis and inhibits cell migration through activation of p53 pathway signaling in melanoma B16F10 cells and A375 cells. Arch Biochem Biophys 2020; 692:108519. [PMID: 32763235 DOI: 10.1016/j.abb.2020.108519] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/10/2020] [Accepted: 07/24/2020] [Indexed: 01/25/2023]
Abstract
Melanoma is a dangerous type of skin cancer that develops from the melanocytes. Activation of p53 in melanoma cells has been validated as a strategy for melanoma therapy. S-Petasin, a dietary sesquiterpene isolated from Petasites japonicus, has been shown to possess multiple biological effects. However, no studies have reported that s-petasin exerted anti-melanoma or inhibited activity in melanoma cells. We investigated the effect of s-petasin in B16F10 cells and A375 cells and the underlying molecular mechanism. S-Petasin exerted a significant anti-proliferation effect on B16F10 cells and A375 cells as measured by the MTT assay and crystal violet staining assay. S-Petasin induced cell apoptosis in B16F10 cells and A375 cells as evidenced by flow cytometry assay and western blot assay. Wound healing assay and transwell cell migration and invasion assay revealed that s-petasin suppressed B16F10 cells and A375 cells migration in vitro. For mechanism study, western blot assay indicated that s-petasin activated the p53 pathway signaling. Furthermore, expression of Bcl-2, Bcl-XL, Bax, MMP-2, MMP-9, p21, CDK4 and cyclin D1 were regulated by s-petasin. Taken together, our data suggest that s-petasin is a novel compound which can induce apoptosis and inhibit cell migration through activation of the p53 pathway signaling in melanoma B16F10 cells and A375 cells.
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Affiliation(s)
- Lu Guo
- Department of Horticultural Bioscience, Pusan National University, Miryang, 50463, Republic of Korea
| | - Jum Soon Kang
- Department of Horticultural Bioscience, Pusan National University, Miryang, 50463, Republic of Korea
| | - Nam Jun Kang
- Department of Horticulture, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Young Whan Choi
- Department of Horticultural Bioscience, Pusan National University, Miryang, 50463, Republic of Korea; Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, Republic of Korea.
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Cohen S, Kramarski L, Levi S, Deshe N, Ben David O, Arbely E. Nonsense mutation-dependent reinitiation of translation in mammalian cells. Nucleic Acids Res 2020; 47:6330-6338. [PMID: 31045216 PMCID: PMC6614817 DOI: 10.1093/nar/gkz319] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 04/16/2019] [Accepted: 04/22/2019] [Indexed: 11/14/2022] Open
Abstract
In-frame stop codons mark the termination of translation. However, post-termination ribosomes can reinitiate translation at downstream AUG codons. In mammals, reinitiation is most efficient when the termination codon is positioned close to the 5′-proximal initiation site and around 78 bases upstream of the reinitiation site. The phenomenon was studied mainly in the context of open reading frames (ORFs) found within the 5′-untranslated region, or polycicstronic viral mRNA. We hypothesized that reinitiation of translation following nonsense mutations within the main ORF of p53 can promote the expression of N-truncated p53 isoforms such as Δ40, Δ133 and Δ160p53. Here, we report that expression of all known N-truncated p53 isoforms by reinitiation is mechanistically feasible, including expression of the previously unidentified variant Δ66p53. Moreover, we found that significant reinitiation of translation can be promoted by nonsense mutations located even 126 codons downstream of the 5′-proximal initiation site, and observed when the reinitiation site is positioned between 6 and 243 bases downstream of the nonsense mutation. We also demonstrate that reinitiation can stabilise p53 mRNA transcripts with a premature termination codon, by allowing such transcripts to evade the nonsense mediated decay pathway. Our data suggest that the expression of N-truncated proteins from alleles carrying a premature termination codon is more prevalent than previously thought.
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Affiliation(s)
- Sarit Cohen
- Department of Chemistry and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
| | - Lior Kramarski
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
| | - Shahar Levi
- Department of Chemistry and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
| | - Noa Deshe
- Department of Chemistry and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
| | - Oshrit Ben David
- Department of Chemistry and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
| | - Eyal Arbely
- Department of Chemistry and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.,Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
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Pavlakis E, Stiewe T. p53's Extended Reach: The Mutant p53 Secretome. Biomolecules 2020; 10:biom10020307. [PMID: 32075247 PMCID: PMC7072272 DOI: 10.3390/biom10020307] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/10/2020] [Accepted: 02/12/2020] [Indexed: 02/08/2023] Open
Abstract
p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization.
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48
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Loss of p53 function at late stages of tumorigenesis confers ARF-dependent vulnerability to p53 reactivation therapy. Proc Natl Acad Sci U S A 2019; 116:22288-22293. [PMID: 31611375 PMCID: PMC6825290 DOI: 10.1073/pnas.1910255116] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Mouse studies demonstrating regression of p53-null tumors following reinstatement of functional p53 have fueled the development of p53 reactivating drugs. However, successful p53 reactivation responses have only been formally demonstrated in tumor models where p53 inactivation served as the initiating event. Our study provides the first proof-of-principle evidence that p53 inactivation at late stages of tumorigenesis can also generate a vulnerability to p53 reactivation. However, this is dependent on intact ARF function highlighting ARF as a potential biomarker for p53 reactivation responses in tumors with late-stage p53 inactivation. It furthermore suggests the use of Mdm2 inhibitors as ARF mimetics for sensitizing ARF-deficient tumors to p53-reactivating drugs. Cancer development is driven by activated oncogenes and loss of tumor suppressors. While oncogene inhibitors have entered routine clinical practice, tumor suppressor reactivation therapy remains to be established. For the most frequently inactivated tumor suppressor p53, genetic mouse models have demonstrated regression of p53-null tumors upon p53 reactivation. While this was shown in tumor models driven by p53 loss as the initiating lesion, many human tumors initially develop in the presence of wild-type p53, acquire aberrations in the p53 pathway to bypass p53-mediated tumor suppression, and inactivate p53 itself only at later stages during metastatic progression or therapy. To explore the efficacy of p53 reactivation in this scenario, we used a reversibly switchable p53 (p53ERTAM) mouse allele to generate Eµ-Myc–driven lymphomas in the presence of active p53 and, after full lymphoma establishment, switched off p53 to model late-stage p53 inactivation. Although these lymphomas had evolved in the presence of active p53, later loss and subsequent p53 reactivation surprisingly activated p53 target genes triggering massive apoptosis, tumor regression, and long-term cure of the majority of animals. Mechanistically, the reactivation response was dependent on Cdkn2a/p19Arf, which is commonly silenced in p53 wild-type lymphomas, but became reexpressed upon late-stage p53 inactivation. Likewise, human p53 wild-type tumor cells with CRISPR-engineered switchable p53ERTAM alleles responded to p53 reactivation when CDKN2A/p14ARF function was restored or mimicked with Mdm2 inhibitors. Together, these experiments provide genetic proof of concept that tumors can respond, in an ARF-dependent manner, to p53 reactivation even if p53 inactivation has occurred late during tumor evolution.
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Abstract
Epithelial-to-mesenchymal transitions (EMTs) require a complete reorganization of cadherin-based cell-cell junctions. p120-catenin binds to the cytoplasmic juxtamembrane domain of classical cadherins and regulates their stability, suggesting that p120-catenin may play an important role in EMTs. Here, we describe the role of p120-catenin in mouse gastrulation, an EMT that can be imaged at cellular resolution and is accessible to genetic manipulation. Mouse embryos that lack all p120-catenin, or that lack p120-catenin in the embryo proper, survive to midgestation. However, mutants have specific defects in gastrulation, including a high rate of p53-dependent cell death, a bifurcation of the posterior axis, and defects in the migration of mesoderm; all are associated with abnormalities in the primitive streak, the site of the EMT. In embryonic day 7.5 (E7.5) mutants, the domain of expression of the streak marker Brachyury (T) expands more than 3-fold, from a narrow strip of posterior cells to encompass more than one-quarter of the embryo. After E7.5, the enlarged T+ domain splits in 2, separated by a mass of mesoderm cells. Brachyury is a direct target of canonical WNT signaling, and the domain of WNT response in p120-catenin mutant embryos, like the T domain, is first expanded, and then split, and high levels of nuclear β-catenin levels are present in the cells of the posterior embryo that are exposed to high levels of WNT ligand. The data suggest that p120-catenin stabilizes the membrane association of β-catenin, thereby preventing accumulation of nuclear β-catenin and excessive activation of the WNT pathway during EMT.
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Lin T, Hou PF, Meng S, Chen F, Jiang T, Li ML, Shi ML, Liu JJ, Zheng JN, Bai J. Emerging Roles of p53 Related lncRNAs in Cancer Progression: A Systematic Review. Int J Biol Sci 2019; 15:1287-1298. [PMID: 31223287 PMCID: PMC6567798 DOI: 10.7150/ijbs.33218] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022] Open
Abstract
p53 is the major mediator of the tumor suppressor response. It participates in apoptosis and senescence and can respond to DNA damage. As a crucial sequence-specific transcription factor, p53 regulates the expression of many genes, such as small noncoding RNAs (ncRNAs), microRNAs, and long ncRNAs (lncRNAs). Given the emergence of novel and high-throughput sequencing technologies, many lncRNAs have been discovered. LncRNAs may function as vital gene regulators in a variety of biological processes through extensive mechanisms. Recently, lncRNAs have been demonstrated to be associated with the p53 regulatory pathway. In this review, we discuss the current and fast growing knowledge about the influence of lncRNAs to the p53 signaling pathway, the different mechanisms by which they affect gene expression in cancer. Our findings show that p53-associated lncRNAs may be used as biomarkers for cancer diagnosis or targets for disease therapy.
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Affiliation(s)
- Tian Lin
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Ping-Fu Hou
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Sen Meng
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Fang Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Tao Jiang
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Min-Le Li
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Mei-Lin Shi
- School of Medical Imaging, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jin-Jin Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Jun-Nian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
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