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Chutake YK, Mayo MF, Dumont N, Filiatrault J, Breitkopf SB, Cho P, Chen D, Dixit VS, Proctor WR, Kuhn EW, Bollinger Martinez S, McDonald AA, Qi J, Hu KN, Karnik R, Growney JD, Sharma K, Schalm SS, Gollerkeri AM, Mainolfi N, Williams JA, Weiss MM. KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors. Mol Cancer Ther 2025; 24:497-510. [PMID: 39648478 PMCID: PMC11962396 DOI: 10.1158/1535-7163.mct-24-0306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 09/05/2024] [Accepted: 12/06/2024] [Indexed: 12/10/2024]
Abstract
Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors have demonstrated limited activity, underscoring an unmet need for a better approach to target MDM2. KT-253 is a highly potent and selective heterobifunctional degrader that overcomes the MDM2 feedback loop seen with small-molecule MDM2/p53 interaction inhibitors and induces apoptosis in a range of hematologic and solid tumor lines. A single intravenous dose of KT-253 triggered rapid apoptosis and sustained tumor regression in p53 wild-type acute myeloid leukemia and acute lymphoblastic leukemia xenograft models. Additionally, a single intravenous dose of KT-253 in combination with standard-of-care venetoclax overcame venetoclax resistance in an acute myeloid leukemia xenograft model. The data herein define the therapeutic potential of KT-253 and support its clinical development in a range of hematologic and solid p53 wild-type malignancies, as a monotherapy and in combination with standard-of-care agents.
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Affiliation(s)
- Yogesh K. Chutake
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Michele F. Mayo
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Nancy Dumont
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Jessica Filiatrault
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | | | - Patricia Cho
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Dapeng Chen
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Vaishali S. Dixit
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - William R. Proctor
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Eric W. Kuhn
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | | | - Alice A. McDonald
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Jianfeng Qi
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Kan-Nian Hu
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Rahul Karnik
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Joseph D. Growney
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Kirti Sharma
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Stefanie S. Schalm
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | | | - Nello Mainolfi
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Juliet A. Williams
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
| | - Matthew M. Weiss
- Kymera Therapeutics, Inc., 500 North Beacon Street, Watertown, Massachusetts
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Li K, Hu W, Wang Y, Chen W, Wen H, Liu J, Li W, Wang B. Searching for novel MDM2/MDMX dual inhibitors through a drug repurposing approach. J Enzyme Inhib Med Chem 2024; 39:2288810. [PMID: 38059334 PMCID: PMC11721856 DOI: 10.1080/14756366.2023.2288810] [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: 07/22/2023] [Revised: 11/10/2023] [Accepted: 11/21/2023] [Indexed: 12/08/2023] Open
Abstract
Disruption of p53-MDM2/MDMX interaction by smaller inhibitors is a promising therapeutic intervention gaining tremendous interest. However, no MDM2/MDMX inhibitors have been marketed so far. Drug repurposing is a validated, practical approach to drug discovery. In this regard, we employed structure-based virtual screening in a reservoir of marketed drugs and identified nintedanib as a new MDM2/MDMX dual inhibitor. The computational structure analysis and biochemical experiments uncover that nintedanib binds MDM2/MDMX similarly to RO2443, a dual MDM2/MDMX inhibitor. Furthermore, the mechanistic study reveals that nintedanib disrupts the physical interaction of p53-MDM2/MDMX, enabling the transcriptional activation of p53 and the subsequent cell cycle arrest and growth inhibition in p53+/+ cancer cells. Lastly, structural minimisation of nintedanib yields H3 with the equivalent potency. In summary, this work provides a solid foundation for reshaping nintedanib as a valuable lead compound for the further design of MDM2/MDMX dual inhibitors.
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Affiliation(s)
- Keting Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenshu Hu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yingjie Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenxing Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongmei Wen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jian Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bo Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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3
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Ballarotto M, Bianconi E, Valentini S, Temperini A, Moretti F, Macchiarulo A. Rational design, synthesis, and biophysical characterization of a peptidic MDM2-MDM4 interaction inhibitor. Bioorg Med Chem 2024; 113:117937. [PMID: 39369567 DOI: 10.1016/j.bmc.2024.117937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/26/2024] [Accepted: 09/30/2024] [Indexed: 10/08/2024]
Abstract
In recent years, the restoration of p53 physiological functions has become an attractive therapeutic approach to develop novel and efficacious cancer therapies. Among other mechanisms, the oncosuppressor protein p53 is functionally regulated by MDM2 through its E3 ligase function. MDM2 promotes p53 ubiquitination and degradation following homodimerization or heterodimerization with MDM4. Recently, we discovered Pep3 (1, Pellegrino et al., 2015), a novel peptidic inhibitor of MDM2 dimerization able to restore p53 oncosuppressive functions both in vitro and in vivo. In this work, we were able to identify the key interactions between peptide 1 and MDM2 RING domain and to design peptide 2, a truncated version of 1 that is still able to bind MDM2. Integrating both computational and biophysical techniques, we show that peptide 2 maintains the conserved peptide 1-MDM2 interactions and is still able to bind to full-length MDM2.
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Affiliation(s)
- Marco Ballarotto
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy
| | - Elisa Bianconi
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy
| | - Sonia Valentini
- PhD program in Sciences of Nutrition, Metabolism, Ageing and Gender Medicine, Catholic University of Rome, Roma, Italy; Institute of Biochemistry and Cell Biology, National Research Council (CNR), Via E. Ramarini, 32, 00015 Monterotondo Scalo, Rome, Italy
| | - Andrea Temperini
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
| | - Fabiola Moretti
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), Via E. Ramarini, 32, 00015 Monterotondo Scalo, Rome, Italy
| | - Antonio Macchiarulo
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
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4
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Liu J, Luo D, Huang H, Mu R, Yuan J, Jiang M, Lin C, Xiang H, Lin X, Song H, Zhang Y. Hippo cooperates with p53 to regulate lung airway mucous cell metaplasia. Dis Model Mech 2024; 17:dmm052074. [PMID: 39428818 PMCID: PMC11603118 DOI: 10.1242/dmm.052074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/12/2024] [Indexed: 10/22/2024] Open
Abstract
Airway mucous cell metaplasia is a significant feature of many chronic airway diseases, such as chronic obstructive pulmonary disease, cystic fibrosis and asthma. However, the mechanisms underlying this process remain poorly understood. Here, we employed in vivo mouse genetic models to demonstrate that Hippo and p53 (encoded by Trp53) cooperate to modulate the differentiation of club cells into goblet cells. We revealed that ablation of Mst1 (Stk4) and Mst2 (Stk3), encoding the core components of Hippo signaling, significantly reduces mucous metaplasia in the lung airways in a lipopolysaccharide (LPS)-induced lung inflammation murine model while promoting club cell proliferation in a Yap (Yap1)-dependent manner. Additionally, we showed that deleting Mst1/2 is sufficient to suppress p53 deficiency-mediated goblet cell metaplasia. Finally, single-cell RNA-sequencing analysis revealed downregulation of YAP and p53 signaling in goblet cells in human airways. These findings underscore the important role of Hippo and p53 signaling in regulating airway mucous metaplasia.
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Affiliation(s)
- Jiangying Liu
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, Inner Mongolia Research Institute, Shenzhen Research Institute, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Dan Luo
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, Inner Mongolia Research Institute, Shenzhen Research Institute, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Haidi Huang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, Inner Mongolia Research Institute, Shenzhen Research Institute, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Rongzi Mu
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, Inner Mongolia Research Institute, Shenzhen Research Institute, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jianghong Yuan
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, Inner Mongolia Research Institute, Shenzhen Research Institute, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ming Jiang
- Center for Genetic Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310030, Zhejiang, China
| | - Chuwen Lin
- Department of Histology and Embryology, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China
| | - Honggang Xiang
- Department of General Surgery, Pudong New Area People's Hospital, Shanghai 201299, China
| | - Xinhua Lin
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Greater Bay Area Institute of Precision Medicine (Guangzhou), Zhongshan Hospital, Fudan University Shanghai, Shanghai 200438, China
| | - Haihan Song
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai 201299, China
- Department of Immunology, DICAT National Biomedical Computation Centre, Vancouver, BC V6B 5A6, Canada
| | - Yongchun Zhang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, Inner Mongolia Research Institute, Shenzhen Research Institute, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
- Department of General Surgery, Pudong New Area People's Hospital, Shanghai 201299, China
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5
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Shah R, Aslam MA, Spanjaard A, de Groot D, Zürcher LM, Altelaar M, Hoekman L, Pritchard CEJ, Pilzecker B, van den Berk PCM, Jacobs H. Dual role of proliferating cell nuclear antigen monoubiquitination in facilitating Fanconi anemia-mediated interstrand crosslink repair. PNAS NEXUS 2024; 3:pgae242. [PMID: 38957451 PMCID: PMC11217772 DOI: 10.1093/pnasnexus/pgae242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 06/03/2024] [Indexed: 07/04/2024]
Abstract
The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated by REV1 or site-specific monoubiquitination of proliferating cell nuclear antigen (PCNA) (PCNA-Ub) at lysine 164 (K164). A PcnaK164R/K164R but not Rev1-/- mutation renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair (1, 2), though the decision making between those remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair, we intercrossed PcnaK164R/+; Fancg-/+ mice. A combined mutation (PcnaK164R/K164R; Fancg-/- ) was found embryonically lethal. RNA-seq of primary double-mutant (DM) mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints. To exclude stress-induced confounders, we utilized a Trp53 knock-down to obtain a model to study ICL repair in depth. Regarding ICL-induced cell toxicity, cell cycle arrest, and replication fork progression, single-mutant and DM MEFs were found equally sensitive, establishing PCNA-Ub to be critical for FA-ICL repair. Immunoprecipitation and spectrometry-based analysis revealed an unknown role of PCNA-Ub in excluding mismatch recognition complex MSH2/MSH6 from being recruited to ICLs. In conclusion, our results uncovered a dual function of PCNA-Ub in ICL repair, i.e. exclude MSH2/MSH6 recruitment to channel the ICL toward canonical FA repair, in addition to its established role in coordinating TLS opposite the unhooked ICL.
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Affiliation(s)
- Ronak Shah
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Muhammad Assad Aslam
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Department/Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Bosan Road, 60800 Multan, Pakistan
| | - Aldo Spanjaard
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Daniel de Groot
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Lisa M Zürcher
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Maarten Altelaar
- Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University and Netherlands Proteomics Centre, Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
| | - Liesbeth Hoekman
- Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Colin E J Pritchard
- Mouse Clinic for Cancer and Aging Transgenic Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Bas Pilzecker
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Paul C M van den Berk
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
| | - Heinz Jacobs
- Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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6
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Santinelli E, Pascale MR, Xie Z, Badar T, Stahl MF, Bewersdorf JP, Gurnari C, Zeidan AM. Targeting apoptosis dysregulation in myeloid malignancies - The promise of a therapeutic revolution. Blood Rev 2023; 62:101130. [PMID: 37679263 DOI: 10.1016/j.blre.2023.101130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/09/2023]
Abstract
In recent years, the therapeutic landscape of myeloid malignancies has been completely revolutionized by the introduction of several new drugs, targeting molecular alterations or pathways crucial for leukemia cells survival. Particularly, many agents targeting apoptosis have been investigated in both pre-clinical and clinical studies. For instance, venetoclax, a pro-apoptotic agent active on BCL-2 signaling, has been successfully used in the treatment of acute myeloid leukemia (AML). The impressive results achieved in this context have made the apoptotic pathway an attractive target also in other myeloid neoplasms, translating the experience of AML. Therefore, several drugs are now under investigation either as single or in combination strategies, due to their synergistic efficacy and capacity to overcome resistance. In this paper, we will review the mechanisms of apoptosis and the specific drugs currently used and under investigation for the treatment of myeloid neoplasia, identifying critical research necessities for the upcoming years.
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Affiliation(s)
- Enrico Santinelli
- Department of Biomedicine and Prevention, PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, 00133 Rome, Italy; Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Maria Rosaria Pascale
- Department of Biomedicine and Prevention, PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Zhuoer Xie
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Talha Badar
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Maximilian F Stahl
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Jan P Bewersdorf
- Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Carmelo Gurnari
- Department of Biomedicine and Prevention, PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, 00133 Rome, Italy; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Amer M Zeidan
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT, USA.
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Hu B, Liu T, Wu Z, Phan SH. P53 regulates CCAAT/Enhancer binding protein β gene expression. Gene 2023; 884:147675. [PMID: 37541559 DOI: 10.1016/j.gene.2023.147675] [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: 05/17/2023] [Revised: 07/13/2023] [Accepted: 07/28/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND The transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) is implicated in diverse processes and diseases. Its two isoforms, namely liver-enriched activator protein (LAP) and liver-enriched inhibitor protein (LIP) are translated from the same mRNA. They share the same C-terminal DNA binding domain except LAP has an extra N-terminal activation domain. Probably due to its higher affinity for its DNA cognate sequences, LIP can inhibit LAP transcriptional activity even at substoichiometric levels. However, the regulatory mechanism of C/EBPβ gene expression and the LAP: LIP ratio is unclear. METHODS In this study, the C/EBPβ promoter sequence was scanned for conserved P53 response element (P53RE), and binding of P53 to the C/EBPβ promoter was tested by Electrophoretic Mobility Shift Assay (EMSA) and chromatin immunoprecipitation assay. P53 over-expression and dominant negative P53 expression plasmids were transfected into rat lung fibroblasts and tested for C/EBPβ gene transcription and expression. Western blot analysis was used to test the regulation of C/EBPβ LAP and LIP isoforms. Constructs containing the LAP 5'untranslated region (5'UTR) or the LIP 5'UTR region were used to test the importance of 5'UTR in the control of C/EBPβ LAP and LIP translation. RESULTS The C/EBPβ promoter sequence was found to contain a conserved P53 response element (P53RE), which binds P53 as demonstrated by Electrophoresis Mobility Shift Assay and chromatin immunoprecipitation assays. P53 over-expression suppressed while dominant negative P53 stimulated C/EBPβ gene transcription and expression. Western blot analysis showed that P53 differentially regulated the translation of the C/EBPβ LAP and LIP isoforms through the regulation of eIF4E and eIF4E-BP1. Further studies with constructs containing the LAP 5'untranslated region (5'UTR) or the LIP 5'UTR region showed that the 5'UTR is important in differential control of C/EBPβ LAP and LIP translation. CONCLUSION Analysis of the effects of P53 on C/EBPβ expression revealed a novel mechanism by which P53 could antagonize the effects of C/EBPβ on its target gene expression. For the first time, P53 is shown to be a repressor of C/EBPβ gene expression at both transcriptional and translational levels, with a differential effect in the magnitude of the effect on LAP vs. LIP isoforms.
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Affiliation(s)
- Biao Hu
- Department of Internal Medicine, University of Michigan Medical School, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
| | - Tianju Liu
- Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109 USA
| | - Zhe Wu
- Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109 USA
| | - Sem H Phan
- Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109 USA.
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8
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Nahar Metu CL, Sutihar SK, Sohel M, Zohora F, Hasan A, Miah MT, Rani Kar T, Hossain MA, Rahman MH. Unraveling the signaling mechanism behind astrocytoma and possible therapeutics strategies: A comprehensive review. Cancer Rep (Hoboken) 2023; 6:e1889. [PMID: 37675821 PMCID: PMC10598261 DOI: 10.1002/cnr2.1889] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/09/2023] [Accepted: 07/28/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying astrocytoma formation has not yet been revealed, although various factors have been investigated. Therefore, our objective was to unravel and summarize our current understanding of molecular genetics and associated signaling pathways with some possible therapeutic strategies for astrocytoma. RECENT FINDINGS In general, four different forms of astrocytoma have been identified in individuals, including circumscribed, diffuse, anaplastic, and multiforme glioblastoma, according to a recent literature review. All types of astrocytoma have a direct connection with some oncogenic signaling cascade. Common signaling is MAPK cascade, including Ras-Raf-ERK, up-regulated with activating EGFR/AKT/PTEN/mTOR and PDGFR. Recent breakthrough studies found that BRAF mutations, including KIAA1549: BRAF and BRAF V600E are responsible for astrocytoma progression. Additionally, cancer progression is influenced by mutations in some tumor suppressor genes, such as the Tp53/ATRX and MGMT mutant. As synthetic medications must cross the blood-brain barrier (BBB), modulating signal systems such as miRNA is the primary option for treating patients with astrocytoma. However, available surgery, radiation therapy, and experimental therapies such as adjuvant therapy, anti-angiogenic therapy, and EGFR-targeting antibody drug are the usual treatment for most types of astrocytoma. Similar to conventional anticancer medications, some phytochemicals slow tumor growth by simultaneously controlling several cellular proteins, including those involved in cell cycle regulation, apoptosis, metastatic spread, tyrosine kinase, growth factor receptor, and antioxidant-related proteins. CONCLUSION In conclusion, cellular and molecular signaling is directly associated with the development of astrocytoma, and a combination of conventional and alternative therapies can improve the malignancy of cancer patients.
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Affiliation(s)
- Chowdhury Lutfun Nahar Metu
- Biochemistry and Molecular BiologyBangabandhu Sheikh Mujibur Rahman Science and Technology UniversityGopalganjBangladesh
| | - Sunita Kumari Sutihar
- Biochemistry and Molecular BiologyBangabandhu Sheikh Mujibur Rahman Science and Technology UniversityGopalganjBangladesh
| | - Md Sohel
- Biochemistry and Molecular BiologyMawlana Bhashani Science and Technology UniversityTangailBangladesh
- Department of Biochemistry and Molecular BiologyPrimeasia UniversityDhakaBangladesh
| | - Fatematuz Zohora
- Department of Pharmacy, Faculty of PharmacyUniversity of DhakaDhakaBangladesh
| | - Akayed Hasan
- Department of PharmacyMawlana Bhashani Science and Technology UniversityTangailBangladesh
| | - Md. Thandu Miah
- Department of PharmacyMawlana Bhashani Science and Technology UniversityTangailBangladesh
| | - Tanu Rani Kar
- Department of Biochemistry and Molecular BiologyPrimeasia UniversityDhakaBangladesh
| | - Md. Arju Hossain
- Department of Biotechnology and Genetic EngineeringMawlana Bhashani Science and Technology UniversityTangailBangladesh
| | - Md Habibur Rahman
- Department of Computer Science and EngineeringIslamic UniversityKushtiaBangladesh
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9
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Bacher S, Schmitz ML. Understanding and Therapeutic Targeting of the p53 Network. Cancers (Basel) 2023; 15:4461. [PMID: 37760430 PMCID: PMC10527094 DOI: 10.3390/cancers15184461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Signaling networks function as highly intertwined regulatory hubs rather than linear cascades with a single endpoint [...].
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Affiliation(s)
| | - M. Lienhard Schmitz
- Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany;
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10
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Ortega-Campos SM, Verdugo-Sivianes EM, Amiama-Roig A, Blanco JR, Carnero A. Interactions of circadian clock genes with the hallmarks of cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188900. [PMID: 37105413 DOI: 10.1016/j.bbcan.2023.188900] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/12/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023]
Abstract
The molecular machinery of the circadian clock regulates the expression of many genes and processes in the organism, allowing the adaptation of cellular activities to the daily light-dark cycles. Disruption of the circadian rhythm can lead to various pathologies, including cancer. Thus, disturbance of the normal circadian clock at both genetic and environmental levels has been described as an independent risk factor for cancer. In addition, researchers have proposed that circadian genes may have a tissue-dependent and/or context-dependent role in tumorigenesis and may function both as tumor suppressors and oncogenes. Finally, circadian clock core genes may trigger or at least be involved in different hallmarks of cancer. Hence, expanding the knowledge of the molecular basis of the circadian clock would be helpful to identify new prognostic markers of tumorigenesis and potential therapeutic targets.
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Affiliation(s)
- Sara M Ortega-Campos
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville 41013, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Eva M Verdugo-Sivianes
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville 41013, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Ana Amiama-Roig
- Hospital Universitario San Pedro, Logroño 26006, Spain; Centro de Investigación Biomédica de La Rioja (CIBIR), Logroño 26006, Spain
| | - José R Blanco
- Hospital Universitario San Pedro, Logroño 26006, Spain; Centro de Investigación Biomédica de La Rioja (CIBIR), Logroño 26006, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville 41013, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid 28029, Spain.
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11
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Covalent targeting the LAS1-NOL9 axis for selective treatment in NPM1 mutant acute myeloid leukemia. Pharmacol Res 2023; 189:106700. [PMID: 36796466 DOI: 10.1016/j.phrs.2023.106700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/01/2023] [Accepted: 02/13/2023] [Indexed: 02/16/2023]
Abstract
Patients with NPM1 gene mutation-associated acute myeloid leukemia (AML), particularly those over the age of 60, have no viable targeted therapeutic choices. In this study, we identified HEN-463, a sesquiterpene lactone derivative specific targets AML with this gene mutation. This compound inhibits the interaction of LAS1-NOL9 by covalently binding to the C264 site of the ribosomal biogenesis-related protein LAS1, which translocates the LAS1 to the cytoplasm, thereby inhibiting the maturation of 28 S rRNA. This has a profound effect on the NPM1-MDM2-p53 pathway and ultimately results in the stabilization of p53. Combining this treatment with the XPO1 inhibitor Selinexor (Sel) can ideally preserve the stabilized p53 in the nucleus, considerably enhancing the efficacy of HEN-463 and addressing Sel's drug resistance. Patients with AML over the age of 60 who possess the NPM1 mutation have an unusually elevated level of LAS1, which has a significant impact on their prognosis. In NPM1-mutant AML cells, decreased LAS1 expression promotes proliferation inhibition, apoptosis, cell differentiation, and cell cycle arrest. This suggests that it may be a therapeutic target for this kind of blood cancer, especially in patients over the age of 60.
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12
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Ivanenkov YA, Kukushkin ME, Beloglazkina AA, Shafikov RR, Barashkin AA, Ayginin AA, Serebryakova MS, Majouga AG, Skvortsov DA, Tafeenko VA, Beloglazkina EK. Synthesis and Biological Evaluation of Novel Dispiro-Indolinones with Anticancer Activity. Molecules 2023; 28:molecules28031325. [PMID: 36770991 PMCID: PMC9919490 DOI: 10.3390/molecules28031325] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/19/2023] [Accepted: 01/26/2023] [Indexed: 02/03/2023] Open
Abstract
Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCTwt, and HCT(-/-). Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC50 = 1.2-3.5 µM) and a reasonable selectivity index (SI = 3-10). Confocal microscopy revealed that the conjugate of propargyl-substituted dispiro-indolinone with the fluorescent dye Sulfo-Cy5-azide was mainly localized in the cytoplasm of HEK293 cells. P388-inoculated mice and HCT116-xenograft BALB/c nude mice were used to evaluate the anticancer activity of compound 29 in vivo. Particularly, the TGRI value for the P388 model was 93% at the final control timepoint. No mortality was registered among the population up to day 31 of the study. In the HCT116 xenograft model, the compound (170 mg/kg, i.p., o.d., 10 days) provided a T/C ratio close to 60% on day 8 after the treatment was completed. The therapeutic index-estimated as LD50/ED50-for compound 29 in mice was ≥2.5. Molecular docking studies were carried out to predict the possible binding modes of the examined molecules towards MDM2 as the feasible biological target. However, such a mechanism was not confirmed by Western blot data and, apparently, the synthesized compounds have a different mechanism of cytotoxic action.
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Affiliation(s)
- Yan A. Ivanenkov
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
- The Federal State Unitary Enterprise Dukhov Automatics Research Institute (VNIIA), 22. ul. Sushchevskaya, 127055 Moscow, Russia
| | - Maxim E. Kukushkin
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
| | | | - Radik R. Shafikov
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, GSP-7, Ulitsa Mklukho-Maklaya 16/10, 17997 Moscow, Russia
- A. N. Belozersky Research Institute of Physico-Chemical Biology MSU, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia
| | - Alexander A. Barashkin
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
| | - Andrey A. Ayginin
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
| | - Marina S. Serebryakova
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
| | - Alexander G. Majouga
- College of New Materials and Nanotechnologies, National University of Science and Technology MISiS, 119049 Moscow, Russia
| | - Dmitry A. Skvortsov
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
| | - Viktor A. Tafeenko
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
| | - Elena K. Beloglazkina
- Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
- Correspondence:
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13
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Deciphering the Role of p53 and TAp73 in Neuroblastoma: From Pathogenesis to Treatment. Cancers (Basel) 2022; 14:cancers14246212. [PMID: 36551697 PMCID: PMC9777536 DOI: 10.3390/cancers14246212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Neuroblastoma (NB) is an embryonic cancer that develops from neural crest stem cells, being one of the most common malignancies in children. The clinical manifestation of this disease is highly variable, ranging from spontaneous regression to increased aggressiveness, which makes it a major therapeutic challenge in pediatric oncology. The p53 family proteins p53 and TAp73 play a key role in protecting cells against genomic instability and malignant transformation. However, in NB, their activities are commonly inhibited by interacting proteins such as murine double minute (MDM)2 and MDMX, mutant p53, ΔNp73, Itch, and Aurora kinase A. The interplay between the p53/TAp73 pathway and N-MYC, a known biomarker of poor prognosis and drug resistance in NB, also proves to be decisive in the pathogenesis of this tumor. More recently, a strong crosstalk between microRNAs (miRNAs) and p53/TAp73 has been established, which has been the focused of great attention because of its potential for developing new therapeutic strategies. Collectively, this review provides an updated overview about the critical role of the p53/TAp73 pathway in the pathogenesis of NB, highlighting encouraging clues for the advance of alternative NB targeted therapies.
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14
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Logotheti S, Pavlopoulou A, Marquardt S, Takan I, Georgakilas AG, Stiewe T. p73 isoforms meet evolution of metastasis. Cancer Metastasis Rev 2022; 41:853-869. [PMID: 35948758 DOI: 10.1007/s10555-022-10057-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/30/2022] [Indexed: 01/25/2023]
Abstract
Cancer largely adheres to Darwinian selection. Evolutionary forces are prominent during metastasis, the final and incurable disease stage, where cells acquire combinations of advantageous phenotypic features and interact with a dynamically changing microenvironment, in order to overcome the metastatic bottlenecks, while therapy exerts additional selective pressures. As a strategy to increase their fitness, tumors often co-opt developmental and tissue-homeostasis programs. Herein, 25 years after its discovery, we review TP73, a sibling of the cardinal tumor-suppressor TP53, through the lens of cancer evolution. The TP73 gene regulates a wide range of processes in embryonic development, tissue homeostasis and cancer via an overwhelming number of functionally divergent isoforms. We suggest that TP73 neither merely mimics TP53 via its p53-like tumor-suppressive functions, nor has black-or-white-type effects, as inferred by the antagonism between several of its isoforms in processes like apoptosis and DNA damage response. Rather, under dynamic conditions of selective pressure, the various p73 isoforms which are often co-expressed within the same cancer cells may work towards a common goal by simultaneously activating isoform-specific transcriptional and non-transcriptional programs. Combinatorial co-option of these programs offers selective advantages that overall increase the likelihood for successfully surpassing the barriers of the metastatic cascade. The p73 functional pleiotropy-based capabilities might be present in subclonal populations and expressed dynamically under changing microenvironmental conditions, thereby supporting clonal expansion and propelling evolution of metastasis. Deciphering the critical p73 isoform patterns along the spatiotemporal axes of tumor evolution could identify strategies to target TP73 for prevention and therapy of cancer metastasis.
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Affiliation(s)
- Stella Logotheti
- DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), 15780, Zografou, Greece.
| | - Athanasia Pavlopoulou
- Izmir Biomedicine and Genome Center (IBG), 35340, Balcova, Izmir, Turkey.,Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, 35340, Balcova, Izmir, Turkey
| | - Stephan Marquardt
- Institute of Translational Medicine for Health Care Systems, Medical School Berlin, Hochschule Für Gesundheit Und Medizin, 14197, Berlin, Germany
| | - Işıl Takan
- Izmir Biomedicine and Genome Center (IBG), 35340, Balcova, Izmir, Turkey.,Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, 35340, Balcova, Izmir, Turkey
| | - Alexandros G Georgakilas
- DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), 15780, Zografou, Greece
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany.,Institute of Lung Health, Giessen, Germany.,German Center for Lung Research (DZL), Philipps-University, Marburg, Germany
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15
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pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation. Nat Commun 2022; 13:6840. [PMID: 36369429 PMCID: PMC9652315 DOI: 10.1038/s41467-022-34529-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/27/2022] [Indexed: 11/13/2022] Open
Abstract
The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.
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Gárate-Rascón M, Recalde M, Rojo C, Fernández-Barrena MG, Ávila MA, Arechederra M, Berasain C. SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease. Int J Mol Sci 2022; 23:ijms232113411. [PMID: 36362191 PMCID: PMC9658179 DOI: 10.3390/ijms232113411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3′ splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.
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Affiliation(s)
- María Gárate-Rascón
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Miriam Recalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Carla Rojo
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Ávila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - María Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-948-194700; Fax: +34-948-194717
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Rahman MM, Sarker MT, Alam Tumpa MA, Yamin M, Islam T, Park MN, Islam MR, Rauf A, Sharma R, Cavalu S, Kim B. Exploring the recent trends in perturbing the cellular signaling pathways in cancer by natural products. Front Pharmacol 2022; 13:950109. [PMID: 36160435 PMCID: PMC9498834 DOI: 10.3389/fphar.2022.950109] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 08/15/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer is commonly thought to be the product of irregular cell division. According to the World Health Organization (WHO), cancer is the major cause of death globally. Nature offers an abundant supply of bioactive compounds with high therapeutic efficacy. Anticancer effects have been studied in a variety of phytochemicals found in nature. When Food and Drug Administration (FDA)-approved anticancer drugs are combined with natural compounds, the effectiveness improves. Several agents have already progressed to clinical trials based on these promising results of natural compounds against various cancer forms. Natural compounds prevent cancer cell proliferation, development, and metastasis by inducing cell cycle arrest, activating intrinsic and extrinsic apoptosis pathways, generating reactive oxygen species (ROS), and down-regulating activated signaling pathways. These natural chemicals are known to affect numerous important cellular signaling pathways, such as NF-B, MAPK, Wnt, Notch, Akt, p53, AR, ER, and many others, to cause cell death signals and induce apoptosis in pre-cancerous or cancer cells without harming normal cells. As a result, non-toxic "natural drugs" taken from nature's bounty could be effective for the prevention of tumor progression and/or therapy of human malignancies, either alone or in combination with conventional treatments. Natural compounds have also been shown in preclinical studies to improve the sensitivity of resistant cancers to currently available chemotherapy agents. To summarize, preclinical and clinical findings against cancer indicate that natural-sourced compounds have promising anticancer efficacy. The vital purpose of these studies is to target cellular signaling pathways in cancer by natural compounds.
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Affiliation(s)
- Md. Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Md. Taslim Sarker
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Mst. Afroza Alam Tumpa
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Md. Yamin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Tamanna Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Md. Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Anbar, Pakistan
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
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Inactivation of tumor suppressor TAp63 by hepatitis B virus X protein in hepatocellular carcinoma. Chin Med J (Engl) 2022; 135:1728-1733. [PMID: 35950770 PMCID: PMC9509107 DOI: 10.1097/cm9.0000000000002283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The hepatitis B virus X (HBx) protein plays a critical role in the initiation and progression of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). In the early stage of the disease, HBx facilitates tumor onset by inactivating the tumor suppressor p53. The p53-encoding gene, however, is frequently mutated or deleted as the cancer progresses to the late stage and, under such circumstance, the p53 homolog TAp63 can harness HCC growth by transactivating several important p53-target genes. METHODS To determine whether HBx regulates TAp63, we performed co-immunoprecipitation assay, real-time quantitative polymerase chain reaction, immunoblotting, and flow cytometry analysis in p53-null cancer cell lines, Hep3B and H1299. RESULTS HBx interacts with the transactivation domain of TAp63, as HBx was co-immunoprecipitated with TAp63 but not with ΔNp63. The interaction between HBx and TAp63 abolished transcriptional activity of TAp63, as evidenced by the reduction of the levels of its target genes p21 and PUMA , consequently leading to restricted apoptosis and augmented proliferation of HCC cells. CONCLUSION HBV induces progression of HCC that harbors defective p53 by inhibiting the tumor suppressor TAp63.
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Wang S, Chen FE. Small-molecule MDM2 inhibitors in clinical trials for cancer therapy. Eur J Med Chem 2022; 236:114334. [DOI: 10.1016/j.ejmech.2022.114334] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/27/2022] [Accepted: 03/28/2022] [Indexed: 02/07/2023]
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Xu N, Lai YY, Chen WM, Jiang H, Wang Y, Wang X, Zhao XS, Huang XJ, Jiang Q, Qin YZ. Independent prognostic significance of TP53 mutations in adult acute myeloid leukaemia with complex karyotype. Int J Lab Hematol 2022; 44:892-899. [PMID: 35505580 DOI: 10.1111/ijlh.13864] [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] [Received: 01/16/2022] [Accepted: 04/19/2022] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Adult acute myeloid leukaemia (AML) patients with complex karyotype (CK) generally have unfavourable outcomes. CK commonly co-exists with characteristic chromosomal and genetic abnormalities such as monosomal karyotype (MK), -17 or 17p- [abn(17p)] and TP53 mutations. Their individual prognostic significance needs to be clarified. METHODS Seventy-three adult CK-AML patients and eleven adult non-CK-AML patients with TP53 mutations (non-CK/TP53mu ) who were diagnosed and received therapy at our institute were enrolled. One hundred and fifty-seven AML cases retrieved from the cancer genome atlas (TCGA) for validation. RESULTS Among CK-AML patients, those with TP53 mutations (CK/TP53mu ) had significantly lower rates of 1-course induction complete remission (CR), 2-year relapse-free survival (RFS) and 2-year overall survival (OS) than those without TP53 mutations (CK/TP53wt ); whereas, abn(17p) did not have the above impacts; MK was significantly associated with a lower 2-year OS rate but was not related to the rates of CR and RFS. Multivariate analysis showed that it were TP53 mutations and treating with chemotherapy alone but not MK and abn(17p) that independently predicted the adverse prognosis for RFS and OS in CK-AML. Furthermore, non-CK/TP53mu patients showed similar rates of CR, RFS and OS to CK/TP53mu patients. Validation using the TCGA cohort showed that CK/TP53mu patients had a significantly lower 2-year OS rate than CK/TP53wt patients, whereas abn(17p) and MK did not impact OS; the 2-year OS rate of patients with CK/TP53wt was similar to that of patients with intermediate-risk cytogenetics. CONCLUSION Adult CK-AML patients have varied risks and TP53 mutations seem to be an independent adverse prognostic factor.
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Affiliation(s)
- Nan Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yue-Yun Lai
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Wen-Min Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Hao Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Su Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Qian Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Ya-Zhen Qin
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
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Klimovich B, Meyer L, Merle N, Neumann M, König AM, Ananikidis N, Keber CU, Elmshäuser S, Timofeev O, Stiewe T. Partial p53 reactivation is sufficient to induce cancer regression. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:80. [PMID: 35232479 PMCID: PMC8889716 DOI: 10.1186/s13046-022-02269-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 01/20/2022] [Indexed: 01/21/2023]
Abstract
Background Impaired p53 function is one of the central molecular features of a tumor cell and even a partial reduction in p53 activity can increase the cancer risk in mice and men. From a therapeutic perspective it is noteworthy that tumor cells often become addicted to the absence of p53 providing a rationale for developing p53 reactivating compounds to treat cancer patients. Unfortunately, many of the compounds that are currently undergoing preclinical and clinical testing fail to fully reactivate mutant p53 proteins, raising the crucial question: how much p53 activity is needed to elicit a therapeutic effect? Methods We have genetically modelled partial p53 reactivation using knock-in mice with inducible expression of the p53 variant E177R. This variant has a reduced ability to bind and transactivate target genes and consequently causes moderate cancer susceptibility. We have generated different syngeneically transplanted and autochthonous mouse models of p53-deficient acute myeloid leukemia and B or T cell lymphoma. After cancer manifestation we have activated E177R expression and analyzed the in vivo therapy response by bioluminescence or magnetic resonance imaging. The molecular response was further characterized in vitro by assays for gene expression, proliferation, senescence, differentiation, apoptosis and clonogenic growth. Results We report the conceptually intriguing observation that the p53 variant E177R, which promotes de novo leukemia and lymphoma formation, inhibits proliferation and viability, induces immune cell infiltration and triggers cancer regression in vivo when introduced into p53-deficient leukemia and lymphomas. p53-deficient cancer cells proved to be so addicted to the absence of p53 that even the low-level activity of E177R is detrimental to cancer growth. Conclusions The observation that a partial loss-of-function p53 variant promotes tumorigenesis in one setting and induces regression in another, underlines the highly context-specific effects of individual p53 mutants. It further highlights the exquisite sensitivity of cancer cells to even small changes in p53 activity and reveals that changes in activity level are more important than the absolute level. As such, the study encourages ongoing research efforts into mutant p53 reactivating drugs by providing genetic proof-of-principle evidence that incomplete p53 reactivation may suffice to elicit a therapeutic response. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02269-6.
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Affiliation(s)
- Boris Klimovich
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany
| | - Laura Meyer
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany
| | - Nastasja Merle
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany
| | - Michelle Neumann
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany
| | - Alexander M König
- Clinic of Diagnostic and Interventional Radiology, Core Facility 7T-small animal MRI, Philipps-University, Marburg, Germany
| | - Nikolaos Ananikidis
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany
| | - Corinna U Keber
- Institute for Pathology, University Hospital Marburg, Philipps-University, Marburg, Germany
| | - Sabrina Elmshäuser
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany
| | - Oleg Timofeev
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany. .,German Center for Lung Research (DZL), Philipps-University, Marburg, Germany.
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany. .,German Center for Lung Research (DZL), Philipps-University, Marburg, Germany. .,Genomics Core Facility, Philipps-University, Marburg, Germany.
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22
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Sivakumar S, Qi S, Cheng N, Sathe AA, Kanchwala M, Kumar A, Evers BM, Xing C, Yu H. TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling. Cell Rep 2022; 38:110395. [PMID: 35172133 PMCID: PMC8904926 DOI: 10.1016/j.celrep.2022.110395] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 11/07/2021] [Accepted: 01/24/2022] [Indexed: 12/13/2022] Open
Abstract
Aneuploidy, defective differentiation, and inactivation of the tumor suppressor TP53 all occur frequently during tumorigenesis. Here, we probe the potential links among these cancer traits by inactivating TP53 in human embryonic stem cells (hESCs). TP53-/- hESCs exhibit increased proliferation rates, mitotic errors, and low-grade structural aneuploidy; produce poorly differentiated immature teratomas in mice; and fail to differentiate into neural progenitor cells (NPCs) in vitro. Genome-wide CRISPR screen reveals requirements of ciliogenesis and sonic hedgehog (Shh) pathways for hESC differentiation into NPCs. TP53 deletion causes abnormal ciliogenesis in neural rosettes. In addition to restraining cell proliferation through CDKN1A, TP53 activates the transcription of BBS9, which encodes a ciliogenesis regulator required for proper Shh signaling and NPC formation. This developmentally regulated transcriptional program of TP53 promotes ciliogenesis, restrains Shh signaling, and commits hESCs to neural lineages.
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Affiliation(s)
- Sushama Sivakumar
- Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA
| | - Shutao Qi
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Ningyan Cheng
- Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA
| | - Adwait A Sathe
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Mohammed Kanchwala
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ashwani Kumar
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Bret M Evers
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Chao Xing
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hongtao Yu
- Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
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23
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Micheloni G, Carnovali M, Millefanti G, Rizzetto M, Moretti V, Montalbano G, Acquati F, Giaroni C, Valli R, Costantino L, Ferrara F, Banfi G, Mariotti M, Porta G. Soy diet induces intestinal inflammation in adult Zebrafish: Role of OTX and P53 family. Int J Exp Pathol 2022; 103:13-22. [PMID: 34725870 PMCID: PMC8781668 DOI: 10.1111/iep.12420] [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: 03/29/2021] [Revised: 09/10/2021] [Accepted: 10/07/2021] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the colon and small intestine, including Crohn's disease and ulcerative colitis. Since Danio rerio is a promising animal model to study gut function, we developed a soy-dependent model of intestinal inflammation in adult zebrafish. The soya bean meal diet was given for 4 weeks and induced an inflammatory process, as demonstrated by morphological changes together with an increased percentage of neutrophils infiltrating the intestinal wall, which developed between the second and fourth week of treatment. Pro-inflammatory genes such as interleukin-1beta, interleukin-8 and tumour necrosis factor alpha were upregulated in the second week and anti-inflammatory genes such as transforming growth factor beta and interleukin-10. Interestingly, an additional expression peak was found for interleukin-8 at the fourth week. Neuronal genes, OTX1 and OTX2, were significantly upregulated in the first two weeks, compatible with the development of the changes in the gut wall. As for the genes of the p53 family such as p53, DNp63 and p73, a statistically significant increase was observed after two weeks of treatment compared with controls. Interestingly, DNp63 and p73 were shown an additional peak after four weeks. Our data demonstrate that soya bean meal diet negatively influences intestinal morphology and immunological function in adult zebrafish showing the features of acute inflammation. Data observed at the fourth week of treatment may suggest initiation of chronic inflammation. Adult zebrafish may represent a promising model to better understand the mechanisms of food-dependent intestinal inflammation.
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Affiliation(s)
- Giovanni Micheloni
- Centro di Medicina GenomicaDepartment of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | | | | | - Manuel Rizzetto
- Department of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | - Vittoria Moretti
- Centro di Medicina GenomicaDepartment of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | - Giuseppe Montalbano
- Centro di Medicina GenomicaDepartment of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | - Francesco Acquati
- Centro di Medicina GenomicaDepartment of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | - Cristina Giaroni
- Department of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | - Roberto Valli
- Centro di Medicina GenomicaDepartment of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | - Lucy Costantino
- Department of Molecular GeneticsCentro Diagnostico ItalianoMilanoItaly
| | - Fulvio Ferrara
- Department of Molecular GeneticsCentro Diagnostico ItalianoMilanoItaly
| | - Giuseppe Banfi
- IRCCS Istituto Ortopedico GaleazziMilanItaly
- Vita‐Salute San Raffaele UniversityMilanItaly
| | - Massimo Mariotti
- IRCCS Istituto Ortopedico GaleazziMilanItaly
- Department of BiomedicalSurgical and Dental SciencesUniversity of MilanMilanItaly
| | - Giovanni Porta
- Centro di Medicina GenomicaDepartment of Medicine and SurgeryUniversity of InsubriaVareseItaly
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24
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microRNA-Mediated Encoding and Decoding of Time-Dependent Signals in Tumorigenesis. Biomolecules 2022; 12:biom12020213. [PMID: 35204714 PMCID: PMC8961662 DOI: 10.3390/biom12020213] [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: 11/22/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 02/01/2023] Open
Abstract
microRNAs, pivotal post-transcriptional regulators of gene expression, in the past decades have caught the attention of researchers for their involvement in different biological processes, ranging from cell development to cancer. Although lots of effort has been devoted to elucidate the topological features and the equilibrium properties of microRNA-mediated motifs, little is known about how the information encoded in frequency, amplitude, duration, and other features of their regulatory signals can affect the resulting gene expression patterns. Here, we review the current knowledge about microRNA-mediated gene regulatory networks characterized by time-dependent input signals, such as pulses, transient inputs, and oscillations. First, we identify the general characteristic of the main motifs underlying temporal patterns. Then, we analyze their impact on two commonly studied oncogenic networks, showing how their dysfunction can lead to tumorigenesis.
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25
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Rethinking IRPs/IRE system in neurodegenerative disorders: Looking beyond iron metabolism. Ageing Res Rev 2022; 73:101511. [PMID: 34767973 DOI: 10.1016/j.arr.2021.101511] [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] [Received: 08/24/2021] [Revised: 10/21/2021] [Accepted: 11/04/2021] [Indexed: 12/11/2022]
Abstract
Iron regulatory proteins (IRPs) and iron regulatory element (IRE) systems are well known in the progression of neurodegenerative disorders by regulating iron related proteins. IRPs are also regulated by iron homeostasis. However, an increasing number of studies have suggested a close relationship between the IRPs/IRE system and non-iron-related neurodegenerative disorders. In this paper, we reviewed that the IRPs/IRE system is not only controlled by iron ions, but also regulated by such factors as post-translational modification, oxygen, nitric oxide (NO), heme, interleukin-1 (IL-1), and metal ions. In addition, by regulating the transcription of non-iron related proteins, the IRPs/IRE system functioned in oxidative metabolism, cell cycle regulation, abnormal proteins aggregation, and neuroinflammation. Finally, by emphasizing the multiple regulations of IRPs/IRE system and its potential relationship with non-iron metabolic neurodegenerative disorders, we provided new strategies for disease treatment targeting IRPs/IRE system.
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26
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de Mey S, Dufait I, De Ridder M. Radioresistance of Human Cancers: Clinical Implications of Genetic Expression Signatures. Front Oncol 2021; 11:761901. [PMID: 34778082 PMCID: PMC8579106 DOI: 10.3389/fonc.2021.761901] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Although radiotherapy is given to more than 50% of cancer patients, little progress has been made in identifying optimal radiotherapy - drug combinations to improve treatment efficacy. Using molecular data from The Cancer Genome Atlas (TCGA), we extracted a total of 1016 cancer patients that received radiotherapy. The patients were diagnosed with head-and-neck (HNSC - 294 patients), cervical (CESC - 166 patients) and breast (BRCA - 549 patients) cancer. We analyzed mRNA expression patterns of 50 hallmark gene sets of the MSigDB collection, which we divided in eight categories based on a shared biological or functional process. Tumor samples were split into upregulated, neutral or downregulated mRNA expression for all gene sets using a gene set analysis (GSEA) pre-ranked analysis and assessed for their clinical relevance. We found a prognostic association between three of the eight gene set categories (Radiobiological, Metabolism and Proliferation) and overall survival in all three cancer types. Furthermore, multiple single associations were revealed in the other categories considered. To the best of our knowledge, our study is the first report suggesting clinical relevance of molecular characterization based on hallmark gene sets to refine radiation strategies.
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Affiliation(s)
- Sven de Mey
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Inès Dufait
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mark De Ridder
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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27
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Lena AM, Foffi E, Agostini M, Mancini M, Annicchiarico-Petruzzelli M, Aberdam D, Velletri T, Shi Y, Melino G, Wang Y, Candi E. TAp63 regulates bone remodeling by modulating the expression of TNFRSF11B/Osteoprotegerin. Cell Cycle 2021; 20:2428-2441. [PMID: 34763601 DOI: 10.1080/15384101.2021.1985772] [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: 12/12/2022] Open
Abstract
ABBREVIATIONS MSC, mesenchymal stem cells; OPG, osteoprotegerin; RUNX2, Run-trelated transcription factor 2.
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Affiliation(s)
- Anna Maria Lena
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy
| | - Erica Foffi
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy
| | - Massimiliano Agostini
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy
| | | | | | | | - Tania Velletri
- Cogentech Società Benefit Srl, Parco Scientifico E Tecnologico Della Sicilia, Catania, Italy
| | - Yufang Shi
- Cas Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.,The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy
| | - Ying Wang
- Cas Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Eleonora Candi
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy.,IDI-IRCCS, Via dei Monti di Creta, Rome, IT
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28
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Abstract
MicroRNAs (miRNAs), a class of small noncoding RNA, posttranscriptionally regulate the expression of genes. Aberrant expression of miRNA is reported in various types of cancer. Since the first report of oncomiR-21 involvement in the glioma, its upregulation was reported in multiple cancers and was allied with high oncogenic property. In addition to the downregulation of tumor suppressor genes, the miR-21 is also associated with cancer resistance to various chemotherapy. The recent research is appraising miR-21 as a promising cancer target and biomarker for early cancer detection. In this review, we briefly explain the biogenesis and regulation of miR-21 in cancer cells. Additionally, the review features the assorted genes/pathways regulated by the miR-21 in various cancer and cancer stem cells.
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29
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Yu J, Lang Q, Zhong C, Wang S, Tian Y. Genome-Wide Identification of Autophagy Prognostic Signature in Pancreatic Cancer. Dose Response 2021; 19:15593258211023260. [PMID: 34262410 PMCID: PMC8252352 DOI: 10.1177/15593258211023260] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 05/07/2021] [Accepted: 05/19/2021] [Indexed: 01/07/2023] Open
Abstract
Background: Autophagy plays a vital role in cancer development. However, there is currently no comprehensive study regarding the effects of autophagy-related genes (ARGs) on pancreatic cancer prognosis. Thus, this study aimed to establish an autophagy-related signature for predicting the prognosis of patients with pancreatic cancer. Methods: We identified and validated differentially-expressed ARGs using data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression project (GTEx) and Expression Omnibus (GEO) database. We performed Cox proportional hazards regression analysis on the differentially-expressed ARGs to develop an autophagy-related signature. We tested the expression of these genes through western blotting and verified their prognostic values through gene expression profiling and interactive analyses (GEPIA). Results: We identified a total of 21 differentially-expressed ARGs and screened 4 OS-related ARGs (TP63, RAB24, APOL1, and PTK6). Both the training and validation sets showed that the autophagy-related signature was more accurate than the Tumor Node Metastasis (TNM) staging system. Moreover, the western blotting result showed that the expression of TP63, APOL1, and PTK6 was high, whereas that of RAB24 was low in cancer tissues. Conclusion: This 4-ARG signature might potentially help in providing personalized therapy to patients with cancer.
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Affiliation(s)
- Jianfa Yu
- Department of General Surgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning, China
| | - Qi Lang
- Department of General Surgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning, China
| | - Chongli Zhong
- Department of General Surgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning, China
| | - Shuang Wang
- Key Laboratory of Higher Education of Liaoning Province, Shenyang, Liaoning, China
| | - Yu Tian
- Department of General Surgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning, China
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30
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Lin CC, Liao WT, Yang TY, Lu HJ, Hsu SL, Wu CC. MicroRNA‑10b modulates cisplatin tolerance by targeting p53 directly in lung cancer cells. Oncol Rep 2021; 46:167. [PMID: 34165168 DOI: 10.3892/or.2021.8118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 03/04/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNA (miRNA or miR)‑10b is an oncogenic miRNA associated with metastasis that is present in various types of tumor, including lung cancer. However, whether miR‑10b is involved in different malignant characteristics, such as drug resistance or stemness, remains unclear. Therefore, the present study investigated whether miR‑10b is an upstream regulator of p53. Ectopic expression of miR‑10b‑agomir decreased the expression of p53 and its downstream effectors, such as Bax and p53 upregulated modulator of apoptosis. Two non‑canonical sites, including 1,580‑1,587 and 2,029‑2,035, located in p53 3'‑untranslated region (UTR) were affected by the presence of miR‑10b. In functional assays, upregulation of the p53 signaling pathway following cisplatin treatment was associated with decreased levels of miR‑10b and upregulation of the luciferase activity of wild‑type, but not 1,584, 2,032‑dual‑mutant, p53 3'‑UTR. The ectopic expression of miR‑10b‑agomir attenuated the stability of p53 3'‑UTR and the expression of p53 and its downstream effectors induced by cisplatin. By contrast, the knockdown of miR‑10b induced the stability of p53 3'‑UTR and increased levels of p53 and the sensitivity of A549 cells to cisplatin treatment. Similar results were also observed for Beas 2B cells. In the clinical investigation, p53 exhibited two distinct associations (cocurrent and countercurrent) with miR‑10b in patients with lung cancer. Patients with lung cancer with low p53 and high miR‑10b levels exhibited the poorest prognosis, while those with high p53 and low miR‑10b exhibited the most favorable prognosis. These findings indicate a novel pathway in which cisplatin induces the levels of p53 by increasing mRNA stability via miR‑10b, indicating a novel oncogenic role of miR‑10b in promoting the malignant characteristics of non‑small cell lung carcinoma.
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Affiliation(s)
- Chen-Chu Lin
- Institute of Medicine, Chung‑Shan Medical University, Taichung 402, Taiwan, R.O.C
| | - Wan-Ting Liao
- Institute of Medicine, Chung‑Shan Medical University, Taichung 402, Taiwan, R.O.C
| | - Tsung-Ying Yang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan, R.O.C
| | - Hsueh-Ju Lu
- Division of Medical Oncology, Department of Internal Medicine, Chung-Shan Medical University Hospital, Taichung 402, Taiwan, R.O.C
| | - Shih-Lan Hsu
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan, R.O.C
| | - Chun-Chi Wu
- Institute of Medicine, Chung‑Shan Medical University, Taichung 402, Taiwan, R.O.C
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31
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Jerafi-Vider A, Bassi I, Moshe N, Tevet Y, Hen G, Splittstoesser D, Shin M, Lawson ND, Yaniv K. VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells. Cell Rep 2021; 35:109255. [PMID: 34133928 PMCID: PMC8220256 DOI: 10.1016/j.celrep.2021.109255] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 03/01/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023] Open
Abstract
The formation of new vessels requires a tight synchronization between proliferation, differentiation, and sprouting. However, how these processes are differentially activated, often by neighboring endothelial cells (ECs), remains unclear. Here, we identify cell cycle progression as a regulator of EC sprouting and differentiation. Using transgenic zebrafish illuminating cell cycle stages, we show that venous and lymphatic precursors sprout from the cardinal vein exclusively in G1 and reveal that cell-cycle arrest is induced in these ECs by overexpression of p53 and the cyclin-dependent kinase (CDK) inhibitors p27 and p21. We further demonstrate that, in vivo, forcing G1 cell-cycle arrest results in enhanced vascular sprouting. Mechanistically, we identify the mitogenic VEGFC/VEGFR3/ERK axis as a direct inducer of cell-cycle arrest in ECs and characterize the cascade of events that render "sprouting-competent" ECs. Overall, our results uncover a mechanism whereby mitogen-controlled cell-cycle arrest boosts sprouting, raising important questions about the use of cell cycle inhibitors in pathological angiogenesis and lymphangiogenesis.
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Affiliation(s)
- Ayelet Jerafi-Vider
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Ivan Bassi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Noga Moshe
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Yaara Tevet
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Gideon Hen
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Daniel Splittstoesser
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Masahiro Shin
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Nathan D Lawson
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Karina Yaniv
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
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32
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Du YY, Lyu KK, Xu MM, Yao WQ, Kang HZ, Han Y, Tang XW, Ma X, Wu XJ, He XF, Wu DP, Liu YJ. [Clinical and prognostic values of TP53 mutation in patients with B-lineage acute lymphoblastic leukemia]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:396-401. [PMID: 34218582 PMCID: PMC8292997 DOI: 10.3760/cma.j.issn.0253-2727.2021.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Indexed: 11/17/2022]
Abstract
Objective: To investigate the survival and prognosis of B-lineage acute lymphoblastic leukemia (B-ALL) patients with TP53 mutation. Methods: The clinical data of 479 newly diagnosed B-ALL patients treated in the First Affiliated Hospital of Soochow University from January 2016 to December 2019 were retrospectively analyzed. Results: Among 479 B-ALL patients, 34 cases (7.1%) were positive for TP53 gene mutation, and a total of 36 TP53 mutations were detected, including 10 frameshift gene mutations (27.8%) , 23 missense mutations (63.9%) and 3 nonsense mutations (8.3%) . A total of 34 (94.4%) mutations were located in the DNA binding domain (exons 5-8) .The average number of mutated genes in patients with TP53 gene mutation (2.3) and the group without TP53 gene mutation (1.1) were statistically different (P<0.001) . The proportion of Ph positive and Ph-like positive patients in the TP53 gene mutation negative group was significantly higher than that of the TP53 mutation positive group, and the difference was statistically significant (P<0.001) . The 3-year OS and EFS rates of the TP53 gene mutation negative group were significantly higher than those of the TP53 gene mutation positive group. The differences in OS and EFS rates between the two groups were statistically significant (χ(2)= 4.694, P = 0.030; χ(2)= 5.080, P= 0.024) . In the multivariate analysis, failure to achieve remission (CR) after one course of induction chemotherapy was an independent adverse prognostic factor affecting OS.Of the 34 patients with TP53 mutation, 16 underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the CR(1) state, and 2 patients with recurrence after transplantation obtained CR(2) after infusion of donor-derived anti-CD19 chimeric antigen receptor T (CAR-T) cells. Among the 11 patients with TP53 gene mutation who relapsed during consolidation chemotherapy, 6 received anti-CD19 CAR T cell therapy, 4 patients achieved remission and minimal residual disease (MRD) turned negative, followed by bridging allo-HSCT, and 2 of them sustained CR. Conclusion: Missense mutations are the most common in B-ALL patients with TP53 gene mutation, and the majority of mutations were located in the DNA binding domain. B-ALL patients with TP53 gene mutation should undergo allo-HSCT as soon as possible after CAR-T cell therapy has cleared the MRD after recurrence. B-ALL patients with TP53 gene mutation still have a higher recurrence rate after allo-HSCT, and the infusion of donor-derived CAR-T cells can achieve better sustained remission.
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Affiliation(s)
- Y Y Du
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - K K Lyu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - M M Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - W Q Yao
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - H Z Kang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - Y Han
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - X W Tang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - X Ma
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - X J Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - X F He
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - D P Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - Y J Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
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Werra UEM, Petzold PT. Epithelioid Angiosarcoma of the Popliteal Artery- Primary or Secondary? A Rare Disease Entity Difficult to Diagnose and Easily Overlooked-Literature Research and Case report. Ann Vasc Surg 2021; 74:524.e1-524.e7. [PMID: 33831522 DOI: 10.1016/j.avsg.2021.02.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/06/2021] [Indexed: 02/02/2023]
Abstract
INTRODUCTION The popliteal artery is a common site of aneurysm formation, whereas sarcomas of the vascular system are very rare. The diagnosis is very difficult to establish. During our literature research we found only seven reports about angiosarcomas of the popliteal artery. Four of them were associated with aneurysms. Because of the poor prognosis early diagnosis is the key to successful treatment. REPORT We present a well-documented case of an 83-year-old patient with an angiosarcoma of the popliteal artery diagnosed as a popliteal artery aneurysm at first. CONCLUSION It is important to think of this rare, highly aggressive tumor entity. Especially the aneurysms that need revision surgery should cause suspicion- histological samples from the aneurysm wall should always be taken.
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Affiliation(s)
| | - Paul Thomas Petzold
- Department of Vascular and Endovascular Surgery, Klinikum Saarbruecken, Saarbruecken, Germany
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Vo NTK. Environmental radiobiology of amphibians - knowledge gaps to be filled using cell lines. Int J Radiat Biol 2021; 98:1034-1046. [PMID: 33428858 DOI: 10.1080/09553002.2021.1872815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Amphibians are facing an unprecedented level of population declines worldwide. The causes run the gamut from habitat loss and succumbing to opportunistic pathogen infections to vulnerability to toxic pollutants and ultraviolet (UV)-B radiation exposure. Anthropogenic activities including Chernobyl and Fukushima nuclear disasters and radioactive waste leakage into the environment raise the background radiation levels. Their immediate and chronic effects on amphibian populations are still being studied. However, the literature on environmental radiation effects on amphibian health still requires a lot more work. Laboratory and field works need to be conducted hand in hand in order to make informative and conclusive analyses to distinguish bad from good and harm from risk or to argue for or against the linear no-threshold model in radioprotection programs. Amphibian cell lines can help seek answers to important questions pertaining environmental radiobiology and amphibian health wherever they can suitably and effectively. The purpose of this work is to show that amphibian cell lines can 'rescue' important knowledge gaps in the literature, especially in the low-dose radiation mechanisms. Presently, there are 142 amphibian cell lines developed from six urodelans and 17 anurans. Amphibian cell lines can help expand and enrich the limited literature on environmental radiation effects on amphibians. They can be used to study mechanisms of radiation actions and discover reliable biomarkers for low-dose exposure. They can be used in environmental radiation monitoring and radioprotection programs. They can be used to determine the effects of co-exposure of IR and other stressors in the environment on amphibian health. They represent an ethical choice for amphibian conservation efforts in the current global amphibian declines. Lessons learned from cellular data can be useful guides to gain a better picture of effects occurring at the amphibian population and ecosystem levels.
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Affiliation(s)
- Nguyen T K Vo
- Department of Biology, McMaster University, Hamilton, Canada.,School of Interdisciplinary Science, McMaster University, Hamilton, Canada
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Chen W, Zhang W, Zhou T, Cai J, Yu Z, Wu Z. A Newly Defined Pyroptosis-Related Gene Signature for the Prognosis of Bladder Cancer. Int J Gen Med 2021; 14:8109-8120. [PMID: 34803395 PMCID: PMC8594790 DOI: 10.2147/ijgm.s337735] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/19/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Bladder cancer (BC), as the most common urinary system tumor type and the main cause of tumor-related death, has an unsatisfactory prognosis. In recent years, related literature has proposed that cell pyroptosis is an inflammatory form of programmed cell death. However, in BC, the relationship between the expression of pyroptosis-related genes and the prognosis has not been elucidated. METHODS We got the RNA sequencing data from TCGA and GEO datasets. Fifty-two pyroptosis-related genes were extracted for further explore. Then, we compared the gene expression levels between the normal bladder and BC tissues. After that, we develop and validate a pyroptosis-related gene prognostic model and made following functional enrichment analysis and single-sample gene set enrichment analysis of the differentially expressed genes between the high- and low-risk groups. RESULTS Twenty-nine differentially expressed genes (DEGs) were found between normal and tumor tissues. Based on the median score calculated by the risk score formula from 8 pyroptosis-related genes, 414 patients were equally divided into low- and high-risk subgroups. The survival probability of BC patients in the high-risk group was significantly lower than that in the low-risk group (P < 0.001). Through multivariate analysis, our risk score is an independent factor predicting OS in BC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis show that high-risk populations are rich in immune-related genes and have a decreased immune status. All the above results have been externally verified from GEO cohort. CONCLUSION Pyroptosis-related genes are closely related to tumor immunity and are a potential prognostic tool for predicting BCs.
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Affiliation(s)
- Weikang Chen
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China
| | - Wenhao Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 325000, People’s Republic of China
- Department of Urology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 325000, People’s Republic of China
| | - Tao Zhou
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China
| | - Jian Cai
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China
| | - Zhixian Yu
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China
- Correspondence: Zhixian Yu; Zhigang Wu Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, No. 2, Fuxue Road Lucheng District, Wenzhou, Zhejiang, 325000, People’s Republic of China Email ;
| | - Zhigang Wu
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China
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The Intricate Role of p53 in Adipocyte Differentiation and Function. Cells 2020; 9:cells9122621. [PMID: 33297294 PMCID: PMC7762213 DOI: 10.3390/cells9122621] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/14/2022] Open
Abstract
For more than three decades, numerous studies have demonstrated the function of p53 in cell cycle, cellular senescence, autophagy, apoptosis, and metabolism. Among diverse functions, the essential role of p53 is to maintain cellular homeostatic response to stress by regulating proliferation and apoptosis. Recently, adipocytes have been studied with increasing intensity owing to the increased prevalence of metabolic diseases posing a serious public health concern and because metabolic dysfunction can directly induce tumorigenesis. The prevalence of metabolic diseases has steadily increased worldwide, and a growing interest in these diseases has led to the focus on the role of p53 in metabolism and adipocyte differentiation with or without metabolic stress. However, our collective understanding of the direct role of p53 in adipocyte differentiation and function remains insufficient. Therefore, this review focuses on the newly discovered roles of p53 in adipocyte differentiation and function.
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Yang WJ, Sun YF, Jin AL, Lv LH, Zhu J, Wang BL, Zhou Y, Zhang CY, Wang H, Hu B, Wang PX, Te L, Pan BS, Zhou J, Fan J, Yang XR, Guo W. BCL11B suppresses tumor progression and stem cell traits in hepatocellular carcinoma by restoring p53 signaling activity. Cell Death Dis 2020; 11:895. [PMID: 33093445 PMCID: PMC7581528 DOI: 10.1038/s41419-020-03115-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 08/03/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022]
Abstract
Accumulating evidence indicates that hepatocellular carcinoma (HCC) tumorigenesis, recurrence, metastasis, and therapeutic resistance are strongly associated with liver cancer stem cells (CSCs), a rare subpopulation of highly tumorigenic cells with self-renewal capacity and differentiation potential. Previous studies identified B cell leukemia/lymphoma-11b (BCL11B) as a novel tumor suppressor with impressive capacity to restrain CSC traits. However, the implications of BCL11B in HCC remain unclear. In this study, we found that low BCL11B expression was an independent indicator for shorter overall survival (OS) and time to recurrence (TTR) for HCC patients with surgical resection. In vitro and in vivo experiments confirmed BCL11B as a tumor suppressor in HCC with inhibitory effects on proliferation, cell cycle progression, apoptosis, and mobility. Furthermore, BCL11B could suppress CSC traits, as evidenced by dramatically decreased tumor spheroid formation, self-renewal potential and drug resistance. A Cignal Finder Array and dual-luciferase activity reporter assays revealed that BCL11B could activate the transcription of P73 via an E2F1-dependent manner. Thus, we concluded that BCL11B is a strong suppressor of retaining CSC traits in HCC. Ectopic expression of BCL11B might be a promising strategy for anti-HCC treatment with the potential to cure HBV-related HCC regardless of P53 mutation status.
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Affiliation(s)
- Wen-Jing Yang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun-Fan Sun
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, P. R. China
| | - An-Li Jin
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li-Hua Lv
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Zhu
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bei-Li Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yan Zhou
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chun-Yan Zhang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bo Hu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, P. R. China
| | - Peng-Xiang Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, P. R. China
| | - Liu Te
- Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 200031, Shanghai, China
| | - Bai-Shen Pan
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, P. R. China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, P. R. China
| | - Xin-Rong Yang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, P. R. China.
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
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Breast-Specific Epigenetic Regulation of DeltaNp73 and Its Role in DNA-Damage-Response of BRCA1-Mutated Human Mammary Epithelial Cells. Cancers (Basel) 2020; 12:cancers12092367. [PMID: 32825620 PMCID: PMC7564633 DOI: 10.3390/cancers12092367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/13/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022] Open
Abstract
The function of BRCA1/2 proteins is essential for maintaining genomic integrity in all cell types. However, why women who carry deleterious germline mutations in BRCA face an extremely high risk of developing breast and ovarian cancers specifically has remained an enigma. We propose that breast-specific epigenetic modifications, which regulate tissue differentiation, could team up with BRCA deficiency and affect tissue susceptibility to cancer. In earlier work, we compared genome-wide methylation profiles of various normal epithelial tissues and identified breast-specific methylated gene promoter regions. Here, we focused on deltaNp73, the truncated isoform of p73, which possesses antiapoptotic and pro-oncogenic functions. We showed that the promoter of deltaNp73 is unmethylated in normal human breast epithelium and methylated in various other normal epithelial tissues and cell types. Accordingly, deltaNp73 was markedly induced by DNA damage in human mammary epithelial cells (HMECs) but not in other epithelial cell types. Moreover, the induction of deltaNp73 protected HMECs from DNA damage-induced cell death, and this effect was more substantial in HMECs from BRCA1 mutation carriers. Notably, when BRCA1 was knocked down in MCF10A, a non-malignant breast epithelial cell line, both deltaNp73 induction and its protective effect from cell death were augmented upon DNA damage. Interestingly, deltaNp73 induction also resulted in inhibition of BRCA1 and BRCA2 expression following DNA damage. In conclusion, breast-specific induction of deltaNp73 promotes survival of BRCA1-deficient mammary epithelial cells upon DNA damage. This might result in the accumulation of genomic alterations and allow the outgrowth of breast cancers. These findings indicate deltaNp73 as a potential modifier of breast cancer susceptibility in BRCA1 mutation carriers and may stimulate novel strategies of prevention and treatment for these high-risk women.
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Zhang W, Tian Y, Gao Q, Li X, Li Y, Zhang J, Yao C, Wang Y, Wang H, Zhao Y, Zhang Q, Li L, Yu Y, Fan Y, Shuai L. Inhibition of Apoptosis Reduces Diploidization of Haploid Mouse Embryonic Stem Cells during Differentiation. Stem Cell Reports 2020; 15:185-197. [PMID: 32502463 PMCID: PMC7363743 DOI: 10.1016/j.stemcr.2020.05.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 05/04/2020] [Accepted: 05/04/2020] [Indexed: 01/19/2023] Open
Abstract
Phenotypes of haploid embryonic stem cells (haESCs) are dominant for recessive traits in mice. However, one major obstacle to their use is self-diploidization in daily culture. Although haESCs maintain haploidy well by deleting p53, whether they can sustain haploidy in differentiated status and the mechanism behind it remain unknown. To address this, we induced p53-deficient haESCs into multiple differentiated lineages maintain haploid status in vitro. Haploid cells also remained in chimeric embryos and teratomas arising from p53-null haESCs. Transcriptome analysis revealed that apoptosis genes were downregulated in p53-null haESCs compared with that in wild-type haESCs. Finally, we knocked out p73, another apoptosis-related gene, and observed stabilization of haploidy in haESCs. These results indicated that the main mechanism of diploidization was apoptosis-related gene-triggered cell death in haploid cell cultures. Thus, we can derive haploid somatic cells by manipulating the apoptosis gene, facilitating genetic screens of lineage-specific development.
haEpiLCs and haNSCLCs differentiated from p53-null haESCs in vitro p53-null haESCs contributed to chimeric embryos and teratoma Downregulation of apoptosis genes resulted in haploidy stabilization Deletion of p73 was also of benefit for haploidy sustenance
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Affiliation(s)
- Wenhao Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Yaru Tian
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Qian Gao
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China; Reproductive Medical Center, Department of Gynecology and Obstetrics, Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
| | - Xu Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Yanni Li
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Jinxin Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Chunmeng Yao
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Yuna Wang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Haoyu Wang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Yiding Zhao
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Qian Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Luyuan Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Yang Yu
- Reproductive Medical Center, Department of Gynecology and Obstetrics, Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China.
| | - Yong Fan
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
| | - Ling Shuai
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China.
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Single and dual target inhibitors based on Bcl-2: Promising anti-tumor agents for cancer therapy. Eur J Med Chem 2020; 201:112446. [PMID: 32563811 DOI: 10.1016/j.ejmech.2020.112446] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 05/08/2020] [Accepted: 05/08/2020] [Indexed: 02/07/2023]
Abstract
B-cell lymphoma-2 (Bcl-2) proteins family is an essential checkpoint in apoptosis. Extensive evidences suggested that overexpression of anti-apoptotic Bcl-2 proteins can be observed in multiple cancer cell lines and primary tumor biopsy samples, which is an important reason for tumor cells to evade apoptosis and further acquire drug resistance for chemotherapy. Hence, down-regulation of anti-apoptotic Bcl-2 proteins is effective for the treatment of cancers. In view that Bcl-2 inhibitors and some other anti-tumor agents, such as HDAC inhibitors and Mdm2 inhibitors, exert synergy effects in tumor cells, it is pointed out that dual-targeting therapies based on these targets are regarded as rational strategies to enhance the effectiveness of single target agents for cancer treatment. This review briefly introduces the apoptosis, the structure of Bcl-2 family proteins, and focuses on the current status and recent advances of Bcl-2 inhibitors and the corresponding SARs of them. Moreover, we discuss the synergisms between Bcl-2 and other anti-tumor targets, and summarize the current dual-target agents.
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Recent Trends of microRNA Significance in Pediatric Population Glioblastoma and Current Knowledge of Micro RNA Function in Glioblastoma Multiforme. Int J Mol Sci 2020; 21:ijms21093046. [PMID: 32349263 PMCID: PMC7246719 DOI: 10.3390/ijms21093046] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Central nervous system tumors are a significant problem for modern medicine because of their location. The explanation of the importance of microRNA (miRNA) in the development of cancerous changes plays an important role in this respect. The first papers describing the presence of miRNA were published in the 1990s. The role of miRNA has been pointed out in many medical conditions such as kidney disease, diabetes, neurodegenerative disorder, arthritis and cancer. There are several miRNAs responsible for invasiveness, apoptosis, resistance to treatment, angiogenesis, proliferation and immunology, and many others. The research conducted in recent years analyzing this group of tumors has shown the important role of miRNA in the course of gliomagenesis. These particles seem to participate in many stages of the development of cancer processes, such as proliferation, angiogenesis, regulation of apoptosis or cell resistance to cytostatics.
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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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Bao Z, He S, Fang D, Guan B, Zhang L, Xiong G, Yang X, He Q, Li X, Zhou L. Prognostic Significance of Murine Double Minute 2 Expression in Tumor Cells in Upper Tract Urothelial Carcinoma: An Analysis of 341 Cases in a Large Chinese Center. Genet Test Mol Biomarkers 2019; 23:797-806. [PMID: 31693454 DOI: 10.1089/gtmb.2019.0126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Aims: The prognostic significance of murine double minute 2 (MDM2) expression remains unknown in patients with upper tract urothelial carcinoma (UTUC). This study was designed to evaluate MDM2 expression and its association with clinicopathological characteristics and tumor outcomes in UTUC patients. Materials and Methods: Expression levels of MDM2 and p53 were determined by immunohistochemistry in a cohort of 341 UTUC patients. Associations of MDM2 and p53 expression levels with clinicopathological characteristics, disease-free survival (DFS), cancer-specific survival (CSS), and intravesical recurrence-free survival (IVRFS) were analyzed. Results: Nuclear expression of MDM2 and p53 were detected in the tumor cells of 129 (37.8%) and 203 (59.5%) patients, respectively. Decreased p53 expression was associated with positive MDM2 staining in tumor cells (p = 0.002). MDM2 expression was correlated with the exposure to aristolochic acids (p = 0.020), better preoperative renal function (p = 0.016), ureter location (p = 0.002), higher pathological T stage (p = 0.006), high tumor grade (p < 0.001), presence of glandular differentiation (p = 0.036), and sarcoma differentiation (p = 0.020). Kaplan-Meier analysis showed that positive MDM2 staining was associated with shorter CSS (p < 0.001), DFS (p < 0.001), and IVRFS (p = 0.020); MDM2+/p53- was associated with shorter CSS (p < 0.001) and DFS (p < 0.001), but not IVRFS (p = 0.145); while CSS, DFS, and IVRFS did not differ significantly between the p53+ and p53- patients (p = 0.307, 0.089, and 0.198, respectively). Multivariate analyses revealed that MDM2 expression in tumor cells independently predicted shorter CSS (p < 0.001; hazard ratio [HR] = 2.600; 95% confidence interval [CI]: 1.625-4.161) and DFS (p < 0.001; HR = 1.863; 95% CI: 1.314-2.641), excepting IVRFS (p = 0.092; HR = 1.590; 95% CI: 0.928-2.726). Conclusions: UTUC patients with elevated MDM2 expression may exhibit more aggressive biological features of the tumor and tend to have shorter CSS and DFS.
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Affiliation(s)
- Zhengqing Bao
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Dong Fang
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Bao Guan
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Lei Zhang
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Gengyan Xiong
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Xinyu Yang
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Qun He
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Centre, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China
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Testis-specific Arf promoter expression in a transposase-aided BAC transgenic mouse model. Mol Biol Rep 2019; 46:6243-6252. [PMID: 31583563 DOI: 10.1007/s11033-019-05063-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/04/2019] [Indexed: 10/25/2022]
Abstract
CDKN2A is an evolutionarily conserved gene encoding proteins implicated in tumor suppression, ocular development, aging, and metabolic diseases. Like the human form, mouse Cdkn2a encodes two distinct proteins-p16Ink4a, which blocks cyclin-dependent kinase activity, and p19Arf, which is best known as a positive regulator of the p53 tumor suppressor-and their functions have been well-studied in genetically engineered mouse models. Relatively little is known about how expression of the two transcripts is controlled in normal development and in certain disease states. To better understand their coordinate and transcript-specific expression in situ, we used a transposase-aided approach to generate a new BAC transgenic mouse model in which the first exons encoding Arf and Ink4a are replaced by fluorescent reporters. We show that mouse embryo fibroblasts generated from the transgenic lines faithfully display induction of each transgenic reporter in cell culture models, and we demonstrate the expected expression of the Arf reporter in the normal testis, one of the few places where that promoter is normally expressed. Interestingly, the TGFβ-2-dependent induction of the Arf reporter in the eye-a process essential for normal eye development-does not occur. Our findings illustrate the value of BAC transgenesis in mapping key regulatory elements in the mouse by revealing the genomic DNA required for Cdkn2a induction in cultured cells and the developing testis, and the apparent lack of elements driving expression in the developing eye.
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Yu L, Yu TT, Young KH. Cross-talk between Myc and p53 in B-cell lymphomas. Chronic Dis Transl Med 2019; 5:139-154. [PMID: 31891126 PMCID: PMC6926120 DOI: 10.1016/j.cdtm.2019.08.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Indexed: 02/07/2023] Open
Abstract
Myc and p53 proteins are closely associated with many physiological cellular functions, including immune response and lymphocyte survival, and are expressed in the lymphoid organs, which are sites for the development and activation of B-cell malignancies. Genetic alterations and other mechanisms resulting in constitutive activation, rearrangement, or mutation of MYC and TP53 contribute to the development of lymphomas, progression and therapy resistance by gene dysregulation, activation of downstream anti-apoptotic pathways, and unfavorable microenvironment interactions. The cross-talk between the Myc and p53 proteins contributes to the inferior prognosis in many types of B-cell lymphomas. In this review, we present the physiological roles of Myc and p53 proteins, and recent advances in understanding the pathological roles of Myc, p53, and their cross-talk in lymphoid neoplasms. In addition, we highlight clinical trials of novel agents that directly or indirectly inhibit Myc and/or p53 protein functions and their signaling pathways. Although, to date, these trials have failed to overcome drug resistance, the new results have highlighted the clinical efficiency of targeting diverse mechanisms of action with the goal of optimizing novel therapeutic opportunities to eradicate lymphoma cells.
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Affiliation(s)
- Li Yu
- Department of Hematology, The Second Affiliated Hospital to Nanchang University, Nanchang, Jiangxi 330006, China
- Hematopathology Division and Pathology Department, Duke University School of Medicine, Durham, NC 27710, USA
| | - Tian-Tian Yu
- Department of Hematology, The Second Affiliated Hospital to Nanchang University, Nanchang, Jiangxi 330006, China
| | - Ken H. Young
- Hematopathology Division and Pathology Department, Duke University School of Medicine, Durham, NC 27710, USA
- Duke University Medical Center and Cancer Institute, Durham, NC 27710, USA
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46
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Zhao J, Tian Y, Zhang H, Qu L, Chen Y, Liu Q, Luo Y, Wu X. p53 Mutant p53 N236S Induces Neural Tube Defects in Female Embryos. Int J Biol Sci 2019; 15:2006-2015. [PMID: 31523200 PMCID: PMC6743294 DOI: 10.7150/ijbs.31451] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 05/26/2019] [Indexed: 12/18/2022] Open
Abstract
The p53 is one of the most important tumor suppressors through surveillance of DNA damages and abnormal proliferation signals, and activation the cell cycle arrest and apoptosis in response to stress. However, the mutation of p53 is known to be oncogenic by both loss of function in inhibiting cell cycle progress and gain of function in promoting abnormal proliferation. In the present study, we have established a knock in mouse model containing an Asn-to-Ser substitution at p53 amino acid 236 by homologous recombination (p53N236S). Other than tumorigenesis phenotype, we found that p53S/S mice displayed female-specific phenotype of open neural tube in brain (exencephaly) and spinal cord (spina bifida). The occurrence rate for embryonic exencephaly is 68.5% in female p53S/S mice, which is much more than that of in p53-/- mice (37.1%) in the same genetic background. Further study found that p53N236S mutation increased neuronal proliferation and decreased neuronal differentiation and apoptosis. To rescue the phenotype, we inhibited cell proliferation by crossing Wrn-/- mice with p53S/S mice. The occurrence of NTDs in p53S/S Wrn-/- mice was 35.2%, thus suggesting that the inhibition of cell proliferation through a Wrn defect partially rescued the exencephaly phenotype in p53S/S mice. We also report that p53S decreased expression of UTX at mRNA and protein level via increasing Xist transcript, result in high female-specific H3K27me3 expression and repressed Mash1 transcription, which facilitating abnormal proliferation, differentiation, and apoptosis, result in the mis-regulation of neurodevelopment and neural tube defects (NTDs).
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Affiliation(s)
- Jinzhi Zhao
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Yingbing Tian
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Huihui Zhang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Lianhua Qu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Yu Chen
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Qing Liu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Ying Luo
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Xiaoming Wu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
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Rodriguez-Ramirez C, Nör JE. p53 and Cell Fate: Sensitizing Head and Neck Cancer Stem Cells to Chemotherapy. Crit Rev Oncog 2019; 23:173-187. [PMID: 30311573 DOI: 10.1615/critrevoncog.2018027353] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Head and neck cancers are deadly diseases that are diagnosed annually in approximately half a million individuals worldwide. Growing evidence supporting a role for cancer stem cells (CSCs) in the pathobiology of head and neck cancers has led to increasing interest in identifying therapeutics to target these cells. Apart from the canonical tumor-suppressor functions of p53, emerging research supports a significant role for this protein in physiological stem cell and CSC maintenance and reprogramming. Therefore, p53 has become a promising target to sensitize head and neck CSCs to chemotherapy. In this review, we highlight the role of p53 in stem cell maintenance and discuss potential implications of targeting p53 to treat patients with head and neck cancers.
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Affiliation(s)
- Christie Rodriguez-Ramirez
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109
| | - Jacques E Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
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48
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Chen WM, Liu H, Li LD, Long LY, Lai YY, Shi HX, Zhao XS, Jiang H, Jiang Q, Liu YR, Qin YZ. [Clinical, molecular and cytogenetic characteristics of newly diagnosed adult acute myeloid patients with TP53 gene mutation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 40:528-531. [PMID: 31340630 PMCID: PMC7342400 DOI: 10.3760/cma.j.issn.0253-2727.2019.06.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Indexed: 12/03/2022]
Affiliation(s)
- W M Chen
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - H Liu
- Xinjiang Uygur Autonomous Region People's Hospital, Urumchi 830001, China
| | - L D Li
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - L Y Long
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - Y Y Lai
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - H X Shi
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - X S Zhao
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - H Jiang
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - Q Jiang
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - Y R Liu
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
| | - Y Z Qin
- Institute of Hematology, Peking University Peoples'Hospital, Beijing 100044, China
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49
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Khurana A, Shafer DA. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther 2019; 12:2903-2910. [PMID: 31289443 PMCID: PMC6563714 DOI: 10.2147/ott.s172315] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Acute myeloid leukemia (AML) is a clonal heterogenous malignancy of the myeloid cells with a poor prognosis lending itself to novel treatment strategies. TP53 is a critical tumor suppressor and plays an essential role in leukemogenesis. Although TP53 is relatively unusual in de novo AML, inactivation of wild-type p53 (WT-p53) is a common event. Murine double minute 2 (MDM2) is a key negative regulator of p53 and its expression; inhibition of MDM2 is postulated to reactivate WT-p53 and its tumor suppressor functions. Nutlins were the first small molecule inhibitors that bind to MDM2 and target its interaction with p53. RG7388 (idasanutlin), a second-generation nutlin, was developed to improve upon the potency and toxicity profile of earlier nutlins. Preliminary data from early phase trials and ongoing studies suggest clinical response with RG7388 (idasanutlin) both in monotherapy and combination strategies in AML. We herein briefly discuss currently approved therapies in AML and review the clinical data for RG7388 (idasanutlin) and MDM2 inhibition as novel treatment strategies in AML. We further describe efficacy and toxicity profile data from completed and ongoing trials of RG7388 (idasanutlin) and other MDM2-p53 inhibitors in development. Many targeted therapies have been approved recently in AML, with a focus on the older and unfit population for intensive induction therapy and in relapsed/refractory disease. The "nutlins", including RG7388 (idasanutlin), merit continued investigation in such settings.
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Affiliation(s)
- Arushi Khurana
- Department of Internal Medicine, Division of Hematology, Oncology & Palliative Care, Virginia Commonwealth University, Richmond, VA 23298, USA,
| | - Danielle A Shafer
- Department of Internal Medicine, Division of Hematology, Oncology & Palliative Care, Virginia Commonwealth University, Richmond, VA 23298, USA,
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50
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Patel A, Soni A, Siddiqi NJ, Sharma P. An insight into the anticancer mechanism of Tribulus terrestris extracts on human breast cancer cells. 3 Biotech 2019; 9:58. [PMID: 30729082 DOI: 10.1007/s13205-019-1585-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 01/17/2019] [Indexed: 01/18/2023] Open
Abstract
Tribulus terrestris (TT), a herb belonging to Zygophyllaceae family is widely used due to its medicinal properties. This study was undertaken to elucidate the anticancer mechanism of TT on MCF-7 breast cancer cells. Cytotoxic effect of the herb was assessed by 3-(4,5-diethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic potential was assessed through DNA fragmentation, TUNEL and caspase 3 activity assays. Expressions of genes regulating the apoptotic pathway were examined by RT-PCR and expression of proteins was analyzed by immunocytochemistry. The result of MTT assay revealed that methanolic and saponin extracts from leaves and seeds of TT were cytotoxic to MCF-7 cells. Cytotoxicity studies on peripheral blood mononuclear cells (PBMC) proved that TT extracts were non-toxic to non-malignant cells. Treatment of human breast cancer MCF-7 cells with seed and leaf methanol and saponin extracts of TT resulted in fragmentation of DNA and induction of apoptosis. This was evident by agarose gel electrophoresis of DNA and TUNNEL assay. The extracts of TT also caused a significant increase in caspase 3 activity in MCF-7 cells. TT extracts caused an induction of intrinsic apoptotic pathway which was evident by the upregulation in the expression of Bax and p53 genes and downregulation in the expression of Bcl-2. FADD, AIF and caspase 8 genes were also upregulated indicating the possible induction of extrinsic apoptotic pathway. Therefore, our results suggest that the Tribulus terrestris (TT) extracts may exert their anticancer activity by both extrinsic and intrinsic apoptotic pathways.
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Affiliation(s)
- Apurva Patel
- 1Department of Biotechnology, Veer Narmad South Gujarat University, Surat, Gujarat 395007 India
| | - Anjali Soni
- 1Department of Biotechnology, Veer Narmad South Gujarat University, Surat, Gujarat 395007 India
| | - Nikhat J Siddiqi
- 2Department of Biochemistry, College of Science, King Saud University, Riyadh, 11495 Saudi Arabia
| | - Preeti Sharma
- 1Department of Biotechnology, Veer Narmad South Gujarat University, Surat, Gujarat 395007 India
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