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Malhotra L, Singh A, Kaur P, Ethayathulla AS. Phenotypical mapping of TP53 unique missense mutations spectrum in human cancers. J Biomol Struct Dyn 2024:1-14. [PMID: 39639563 DOI: 10.1080/07391102.2024.2435060] [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: 01/11/2024] [Accepted: 04/04/2024] [Indexed: 12/07/2024]
Abstract
The p53 tumor suppressor is one of the most mutated genes responsible for tumorigenesis in most human cancers. Out of 29,891 genomic mutations reported in the TP53 Database (https://tp53.isb-cgc.org/), 1,297 are identified as unique missense somatic mutations excluding frameshift, intronic, deletion, nonsense, silent, splice, and other unknown mutations. We have comprehensively analyzed all these 1,297 unique missense mutations and created a phenotypical map based on the distribution of mutations in each domain, the functional state of the protein, and their occurrence in different types of tissues and organs. Our mutation map shows that almost 118 unique missense mutations are reported in the transactivation and proline-rich domains, 1,065 in the central DNA-binding domains, and 113 in the oligomerization and regulatory domains. Based on the phenotype, these mutations are subdivided into 46 super trans, 491 functional, 315 partially functional, and 415 non-functional mutations. The prevalence of these mutations was checked in 71 different types of tissues and found that the mutant R248Q is reported in 51 types of tissues followed by R175H and R273H in 46 types. We correlated the potential impact of mutation in target gene transcription and regulation with nucleosomal DNA and RNA-Pol II complexes. We have discussed the impact of mutation at post-translational modification sites in the structure and function of p53 highlighting the potential therapeutic drug targets with tremendous clinical applications.
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Affiliation(s)
- Lakshay Malhotra
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
- Department of Biochemistry, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Alankrita Singh
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Punit Kaur
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Abdul S Ethayathulla
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
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Buckley NA, Craxton A, Sun XM, Panatta E, Pinon LG, Beier S, Kalmar L, Llodrá J, Morone N, Amelio I, Melino G, Martins LM, MacFarlane M. TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis. Cell Death Dis 2024; 15:807. [PMID: 39516459 PMCID: PMC11549358 DOI: 10.1038/s41419-024-07130-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/19/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024]
Abstract
Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic Atrophy 1 (OPA1), a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy production via oxidative phosphorylation. Owing to the role of OPA1 in modulating cytochrome c release, TAp73-/- cells display an increased sensitivity to apoptotic cell death, e.g., via BH3-mimetics. We additionally show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells of Trp73-/- (global p73 knock-out) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this, Trp73 and OPA1 gene expression is decreased in chronic obstructive pulmonary disease (COPD) patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. Our findings also add to the growing body of evidence for growth-promoting roles of TAp73 isoforms.
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Affiliation(s)
- Niall A Buckley
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
- Safety Sciences, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Andrew Craxton
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Xiao-Ming Sun
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Emanuele Panatta
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | | | - Sina Beier
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Lajos Kalmar
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Jaime Llodrá
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
| | | | - Ivano Amelio
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
- Division for Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Gerry Melino
- MRC Toxicology Unit, University of Cambridge, Cambridge, UK
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
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Zhang Y, Yang Y, Hou Y, Yan W, Zhang X, Huang X, Song Q, He F, Wang J, Sun A, Tian C. ZNF8 promotes progression of gastrointestinal cancers via a p53-dependent mechanism. Cell Signal 2024; 123:111354. [PMID: 39173856 DOI: 10.1016/j.cellsig.2024.111354] [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: 03/20/2024] [Revised: 07/09/2024] [Accepted: 08/18/2024] [Indexed: 08/24/2024]
Abstract
p53 is a critical tumor suppressor, and the disruption of its normal function is often a prerequisite for the development or progression of tumors. Our previous works revealed that multiple members of Krüppel-associated box (KRAB) domain zinc-finger proteins (KZFPs) family regulate p53 transcriptional activity by interacting with it. But the tumor biology functions of these members have not been fully elucidated. Here, the pan-cancer analysis related to gastrointestinal cancers (GICs) revealed that ZNF8, a p53-interacting protein, is an unfavorable prognostic factor for patients with malignancies. ZNF8 interacts with p53 and further depresses its transcriptional activity in colon cancer cells. The knockdown of ZNF8 or the overexpression of ZNF8 inhibits or facilitates the in vitro colony formation, migration, invasion, and angiogenesis of p53+/+ colon cancer HCT116 cells, HepG2 cells and EC109 cells rather than p53-/- colon cancer HCT116 cells and p53-knockout HepG2 cells, respectively. Xenograft experiments conducted in vivo also showed that the knockdown of ZNF8 in p53+/+ but not in p53-/- HCT116 cells curbs the tumor growth and metastasis to lung, leading to an extended life span for tumor-bearing mice. Clinically, two independent immunohistochemistry cohorts of colon cancer and esophageal cancer also indicated that ZNF8 is higher expression in carcinoma tissues than adjacent tissues and this is associated with worse overall survival outcomes in patients without harboring p53 mutation. Together, our results provide insight into the p53-specific tumor oncogenic function of ZNF8. ZNF8 may prove to be a potential target for GICs treatment.
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Affiliation(s)
- Yiming Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China
| | - Yingchuan Yang
- College of Life Sciences, Shandong Normal University, Jinan 250014, China
| | - Yushan Hou
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China
| | - Wei Yan
- The First Medical Center of Chinese PLA General Hospital, Beijing 100036, China
| | - Xiuyuan Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China
| | - Xiaofen Huang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; College of Life Sciences, Hebei University, Baoding 071002, Hebei, China
| | - Qin Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; College of Life Sciences, Hebei University, Baoding 071002, Hebei, China
| | - Fuchu He
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China
| | - Jian Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China; College of Life Sciences, Hebei University, Baoding 071002, Hebei, China.
| | - Aihua Sun
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China; College of Life Sciences, Hebei University, Baoding 071002, Hebei, China.
| | - Chunyan Tian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Research Unit of Proteomics Dirven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China; College of Life Sciences, Hebei University, Baoding 071002, Hebei, China.
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Qayoom H, Mir MA. Mutant P53 modulation by cryptolepine through cell cycle arrest and apoptosis in triple negative breast cancer. Biomed Pharmacother 2024; 179:117351. [PMID: 39216450 DOI: 10.1016/j.biopha.2024.117351] [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: 07/21/2024] [Revised: 08/13/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Triple Negative Breast cancer is an aggressive breast cancer subtype. It has a more aggressive clinical course, an earlier age of onset, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments however remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60-88 % of TNBC, translating p53 into the clinical situation is particularly important in TNBC. In this study, we screened and evaluated the therapeutic potential of cryptolepine (CRP) in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic targeting TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported before. METHODS MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate the cryptolepine's effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis mechanism. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay. RESULTS In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism by which cryptolepine induces intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability, hence activating its tumor suppressing potential significantly. CONCLUSION Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability.
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Affiliation(s)
- Hina Qayoom
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Manzoor A Mir
- Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India.
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Mehrtabar E, Khalaji A, Pandeh M, Farhoudian A, Shafiee N, Shafiee A, Ojaghlou F, Mahdavi P, Soleymani-Goloujeh M. Impact of microRNA variants on PI3K/AKT signaling in triple-negative breast cancer: comprehensive review. Med Oncol 2024; 41:222. [PMID: 39120634 DOI: 10.1007/s12032-024-02469-4] [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: 06/10/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024]
Abstract
Breast cancer (BC) is a significant cause of cancer-related mortality, and triple-negative breast cancer (TNBC) is a particularly aggressive subtype associated with high mortality rates, especially among younger females. TNBC poses a considerable clinical challenge due to its aggressive tumor behavior and limited therapeutic options. Aberrations within the PI3K/AKT pathway are prevalent in TNBC and correlate with increased therapeutic intervention resistance and poor outcomes. MicroRNAs (miRs) have emerged as crucial PI3K/AKT pathway regulators influencing various cellular processes involved in TNBC pathogenesis. The levels of miRs, including miR-193, miR-4649-5p, and miR-449a, undergo notable changes in TNBC tumor tissues, emphasizing their significance in cancer biology. This review explored the intricate interplay between miR variants and PI3K/AKT signaling in TNBC. The review focused on the molecular mechanisms underlying miR-mediated dysregulation of this pathway and highlighted specific miRs and their targets. In addition, we explore the clinical implications of miR dysregulation in TNBC, particularly its correlation with TNBC prognosis and therapeutic resistance. Elucidating the roles of miRs in modulating the PI3K/AKT signaling pathway will enhance our understanding of TNBC biology and unveil potential therapeutic targets. This comprehensive review aims to discuss current knowledge and open promising avenues for future research, ultimately facilitating the development of precise and effective treatments for patients with TNBC.
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Affiliation(s)
- Ehsan Mehrtabar
- Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran
| | - Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mojtaba Pandeh
- School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Aram Farhoudian
- School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Nadia Shafiee
- Children's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Atefe Shafiee
- Board-Certified Cardiologist, Rajaie Cardiovascular Medical and Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ojaghlou
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parinaz Mahdavi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Soleymani-Goloujeh
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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Benedetti R, Romeo MA, Arena A, Gilardini Montani MS, D’Orazi G, Cirone M. ATF6 supports lysosomal function in tumor cells to enable ER stress-activated macroautophagy and CMA: impact on mutant TP53 expression. Autophagy 2024; 20:1854-1867. [PMID: 38566314 PMCID: PMC11262222 DOI: 10.1080/15548627.2024.2338577] [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: 08/08/2023] [Revised: 03/20/2024] [Accepted: 03/31/2024] [Indexed: 04/04/2024] Open
Abstract
The inhibition of the unfolded protein response (UPR), which usually protects cancer cells from stress, may be exploited to potentiate the cytotoxic effect of drugs inducing ER stress. However, in this study, we found that ER stress and UPR activation by thapsigargin or tunicamycin promoted the lysosomal degradation of mutant (MUT) TP53 and that the inhibition of the UPR sensor ATF6, but not of ERN1/IRE1 or EIF2AK3/PERK, counteracted such an effect. ATF6 activation was indeed required to sustain the function of lysosomes, enabling the execution of chaperone-mediated autophagy (CMA) as well as of macroautophagy, processes involved in the degradation of MUT TP53 in stressed cancer cells. At the molecular level, by pharmacological and genetic approaches, we demonstrated that the inhibition of ATF6 correlated with the activation of MTOR and with TFEB and LAMP1 downregulation in thapsigargin-treated MUT TP53 carrying cells. We hypothesize that the rescue of MUT TP53 expression by ATF6 inhibition, could further activate MTOR and maintain lysosomal dysfunction, further inhibiting MUT TP53 degradation, in a vicious circle. The findings of this study suggest that the presence of MUT TP53, which often exerts oncogenic properties, should be considered before approaching treatments combining ER stressors with ATF6 inhibitors against cancer cells, while it could represent a promising strategy against cancer cells that harbor WT TP53.
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Affiliation(s)
- Rossella Benedetti
- Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy
| | - Maria Anele Romeo
- Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy
| | - Andrea Arena
- Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy
| | | | - Gabriella D’Orazi
- Department of Neurosciences, Imaging and Clinical Sciences, University “G. D’Annunzio”, Chieti, Italy
| | - Mara Cirone
- Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy
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Ikliptikawati DK, Makiyama K, Hazawa M, Wong RW. Unlocking the Gateway: The Spatio-Temporal Dynamics of the p53 Family Driven by the Nuclear Pores and Its Implication for the Therapeutic Approach in Cancer. Int J Mol Sci 2024; 25:7465. [PMID: 39000572 PMCID: PMC11242911 DOI: 10.3390/ijms25137465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024] Open
Abstract
The p53 family remains a captivating focus of an extensive number of current studies. Accumulating evidence indicates that p53 abnormalities rank among the most prevalent in cancer. Given the numerous existing studies, which mostly focus on the mutations, expression profiles, and functional perturbations exhibited by members of the p53 family across diverse malignancies, this review will concentrate more on less explored facets regarding p53 activation and stabilization by the nuclear pore complex (NPC) in cancer, drawing on several studies. p53 integrates a broad spectrum of signals and is subject to diverse regulatory mechanisms to enact the necessary cellular response. It is widely acknowledged that each stage of p53 regulation, from synthesis to degradation, significantly influences its functionality in executing specific tasks. Over recent decades, a large body of data has established that mechanisms of regulation, closely linked with protein activation and stabilization, involve intricate interactions with various cellular components. These often transcend canonical regulatory pathways. This new knowledge has expanded from the regulation of genes themselves to epigenomics and proteomics, whereby interaction partners increase in number and complexity compared with earlier paradigms. Specifically, studies have recently shown the involvement of the NPC protein in such complex interactions, underscoring the further complexity of p53 regulation. Furthermore, we also discuss therapeutic strategies based on recent developments in this field in combination with established targeted therapies.
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Affiliation(s)
- Dini Kurnia Ikliptikawati
- Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan;
| | - Kei Makiyama
- Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
| | - Masaharu Hazawa
- Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan;
- Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
- WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
| | - Richard W. Wong
- Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan;
- Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
- WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 9201192, Japan
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8
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Wang L, Liu H, Feng Y, Liu X, Wang Y, Liu Y, Li H, Zhang Y. Decoding the immune landscape: a comprehensive analysis of immune-associated biomarkers in cervical carcinoma and their implications for immunotherapy strategies. Front Genet 2024; 15:1340569. [PMID: 38933923 PMCID: PMC11199791 DOI: 10.3389/fgene.2024.1340569] [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: 11/23/2023] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Background and aims Cervical cancer, a prevalent gynecological malignant tumor, poses a significant threat to women's health and lives. Immune checkpoint inhibitor (ICI) therapy has emerged as a promising avenue for treating cervical cancer. For patients with persistent or recurrent metastatic cervical cancer, If the sequence of dead receptor ligand-1 (PD-L1) is positive, ICI show significant clinical efficacy. PD-L1 expression serves as a valuable biomarker for assessing ICI therapeutic efficacy. However, the complex tumor immune microenvironment (TIME), encompassing immune cell composition and tumor-infiltrating lymphocyte (TIL) status, also exerts a profound influence on tumor immunity and prognosis. Given the remarkable strides made by ICI treatments in improving the survival rates of cervical cancer patients, it becomes essential to identify a comprehensive biomarker that integrates various TIME aspects to enhance the effectiveness of ICI treatment. Therefore, the quest for biomarkers linked to multiple facets of TIME in cervical cancer is a vital pursuit. Methods In this study, we have developed an Immune-Associated Gene Prognostic Index (IRGPI) with remarkable prognostic value specifically for cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). The Cancer Genome Atlas CESC dataset (n = 305) was meticulously analyzed to pinpoint key immune-related genes via weighted gene co-expression network analysis and differential gene expression assays. Subsequently, we employed Cox regression analysis to construct the IRGPI. Furthermore, the composition of immune cells and TIL status were examined using CIBERSORT and TIDE. Tumor expression of Epigen, LCN10, and P73 were determined with immunohistochemistry. Results The resulting IRGPI, composed of EPGN, LCN10, and TP73 genes, displayed a strong negative correlation with patient survival. The discovery was validated with a patient cohort from our hospital. The IRGPI not only predicts the composition of immune cell subtypes such as Macrophages M1, NK cells, Mast cells, Plasma cells, Neutrophils, Dendritic cells, T cells CD8, and T cells CD4 within CESC, but also indicates TIL exclusion, dysfunction, and PD-1 and PD-L1 expression. Therefore, the IRGPI emerges as a promising biomarker not only for prognostic assessment but also for characterizing multiple immune features in CESC. Additionally, our results underscored the significant associations between the IRGPI and immune cell composition, TIL exclusion, and dysfunction, along with PD-1 and PD-L1 expression in the TIME. Conclusion Consequently, the IRGPI stands out as a biomarker intimately connected to both the survival and TIME status of CESC patients, offering potential insights into immunotherapy strategies for CESC.
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Affiliation(s)
- Le Wang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Huatian Liu
- Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yue Feng
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Xueting Liu
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuan Wang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yujie Liu
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hao Li
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Yunyan Zhang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
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Vojsovič M, Kratochvilová L, Valková N, Šislerová L, El Rashed Z, Menichini P, Inga A, Monti P, Brázda V. Transactivation by partial function P53 family mutants is increased by the presence of G-quadruplexes at a promoter site. Biochimie 2024; 216:14-23. [PMID: 37838351 DOI: 10.1016/j.biochi.2023.09.026] [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: 07/19/2023] [Revised: 09/04/2023] [Accepted: 09/27/2023] [Indexed: 10/16/2023]
Abstract
The effect of mutations in the P53 family of transcription factors on their biological functions, including partial or complete loss of transcriptional activity, has been confirmed several times. At present, P53 family proteins showing partial loss of activity appear to be promising potential candidates for the development of novel therapeutic strategies which could restore their transcriptional activity. In this context, it is important to employ tools to precisely monitor their activity; in relation to this, non-canonical DNA secondary structures in promoters including G-quadruplexes (G4s) were shown to influence the activity of transcription factors. Here, we used a defined yeast assay to evaluate the impact of differently modeled G4 forming sequences on a panel of partial function P53 family mutant proteins. Specifically, a 22-mer G4 prone sequence (derived from the KSHV virus) and five derivatives that progressively mutate characteristic guanine stretches were placed upstream of a minimal promoter, adjacent to a P53 response element in otherwise isogenic yeast luciferase reporter strains. The transactivation ability of cancer-associated P53 (TA-P53α: A161T, R213L, N235S, V272L, R282W, R283C, R337C, R337H, and G360V) or Ectodermal Dyplasia syndromes-related P63 mutant proteins (ΔN-P63α: G134D, G134V and inR155) were tested. Our results show that the presence of G4 forming sequences can increase the transactivation ability of partial function P53 family proteins. These observations are pointing to the importance of DNA structural characteristics for accurate classification of P53 family proteins functionality in the context of the wide variety of TP53 and TP63 germline and somatic mutations.
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Affiliation(s)
- Matúš Vojsovič
- Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61200, Brno, Czech Republic; Department of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkyňova 118, 61200, Brno, Czech Republic.
| | - Libuše Kratochvilová
- Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61200, Brno, Czech Republic; Department of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkyňova 118, 61200, Brno, Czech Republic.
| | - Natália Valková
- Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61200, Brno, Czech Republic.
| | - Lucie Šislerová
- Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61200, Brno, Czech Republic; Department of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkyňova 118, 61200, Brno, Czech Republic.
| | - Zeinab El Rashed
- Gene Expression Regulation, IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.
| | - Paola Menichini
- Mutagenesis and Cancer Prevention, IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.
| | - Alberto Inga
- Laboratory of Transcriptional Networks, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy.
| | - Paola Monti
- Mutagenesis and Cancer Prevention, IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.
| | - Václav Brázda
- Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61200, Brno, Czech Republic; Department of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkyňova 118, 61200, Brno, Czech Republic.
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10
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Le MT, Nguyen HT, Nguyen XH, Do XH, Mai BT, Ngoc Nguyen HT, Trang Than UT, Nguyen TH. Regulation and therapeutic potentials of microRNAs to non-small cell lung cancer. Heliyon 2023; 9:e22080. [PMID: 38058618 PMCID: PMC10696070 DOI: 10.1016/j.heliyon.2023.e22080] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 12/08/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80%-85% of total cases and leading to millions of deaths worldwide. Drug resistance is the primary cause of treatment failure in NSCLC, which urges scientists to develop advanced approaches for NSCLC treatment. Among novel approaches, the miRNA-based method has emerged as a potential approach as it allows researchers to modulate target gene expression. Subsequently, cell behaviors are altered, which leads to the death and the depletion of cancer cells. It has been reported that miRNAs possess the capacity to regulate multiple genes that are involved in various signaling pathways, including the phosphoinositide 3-kinase, receptor tyrosine kinase/rat sarcoma virus/mitogen-activated protein kinase, wingless/integrated, retinoblastoma, p53, transforming growth factor β, and nuclear factor-kappa B pathways. Dysregulation of these signaling pathways in NSCLC results in abnormal cell proliferation, tissue invasion, and drug resistance while inhibiting apoptosis. Thus, understanding the roles of miRNAs in regulating these signaling pathways may enable the development of novel NSCLC treatment therapies. However, a comprehensive review of potential miRNAs in NSCLC treatment has been lacking. Therefore, this review aims to fill the gap by summarizing the up-to-date information on miRNAs regarding their targets, impact on cancer-associated pathways, and prospective outcomes in treating NSCLC. We also discuss current technologies for delivering miRNAs to the target cells, including virus-based, non-viral, and emerging extracellular vesicle-based delivery systems. This knowledge will support future studies to develop an innovative miRNA-based therapy and select a suitable carrier to treat NSCLC effectively.
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Affiliation(s)
- Mai Thi Le
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
- Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, 100000, Viet Nam
| | - Huyen-Thu Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Xuan-Hung Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
- College of Health Sciences, Vin University, Hanoi, 100000, Viet Nam
- Vinmec-VinUni Institute of Immunology, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Xuan-Hai Do
- Department of Gastroenterology, 108 Military Central Hospital, Hanoi, Viet Nam
| | - Binh Thanh Mai
- Department of Practical and Experimental Surgery, Vietnam Military Medical University, 160 Phung Hung Street, Phuc La, Ha Dong, Hanoi, Viet Nam
| | - Ha Thi Ngoc Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Uyen Thi Trang Than
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
- Vinmec-VinUni Institute of Immunology, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Thanh-Hong Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
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11
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Senapati J, Muftuoglu M, Ishizawa J, Abbas HA, Loghavi S, Borthakur G, Yilmaz M, Issa GC, Dara SI, Basyal M, Li L, Naqvi K, Pourebrahim R, Jabbour EJ, Kornblau SM, Short NJ, Pemmaraju N, Garcia-Manero G, Ravandi F, Khoury J, Daver N, Kantarjian HM, Andreeff M, DiNardo CD. A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis. Blood Cancer J 2023; 13:101. [PMID: 37386016 PMCID: PMC10310786 DOI: 10.1038/s41408-023-00871-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/02/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response.
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Affiliation(s)
- Jayastu Senapati
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Jo Ishizawa
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Hussein A Abbas
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Sanam Loghavi
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA
| | - Gautam Borthakur
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Musa Yilmaz
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Ghayas C Issa
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Samuel I Dara
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Mahesh Basyal
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Li Li
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Kiran Naqvi
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Elias J Jabbour
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Nicholas J Short
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Naveen Pemmaraju
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Farhad Ravandi
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph Khoury
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA
| | - Naval Daver
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Michael Andreeff
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
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12
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Montero-Calle A, Garranzo-Asensio M, Torrente-Rodríguez RM, Ruiz-Valdepeñas Montiel V, Poves C, Dziaková J, Sanz R, Díaz del Arco C, Pingarrón JM, Fernández-Aceñero MJ, Campuzano S, Barderas R. p53 and p63 Proteoforms Derived from Alternative Splicing Possess Differential Seroreactivity in Colorectal Cancer with Distinct Diagnostic Ability from the Canonical Proteins. Cancers (Basel) 2023; 15:2102. [PMID: 37046764 PMCID: PMC10092954 DOI: 10.3390/cancers15072102] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second most frequent cause of cancer-related death worldwide. The detection in plasma samples of autoantibodies against specific tumor-associated antigens has been demonstrated to be useful for the early diagnosis of CRC by liquid biopsy. However, new studies related to the humoral immune response in cancer are needed to enable blood-based diagnosis of the disease. Here, our aim was to characterize the humoral immune response associated with the different p53 and p63 proteoforms derived from alternative splicing and previously described as aberrantly expressed in CRC. Thus, here we investigated the diagnostic ability of the twelve p53 proteoforms and the eight p63 proteoforms described to date, and their specific N-terminal and C-terminal end peptides, by means of luminescence HaloTag beads immunoassays. Full-length proteoforms or specific peptides were cloned as HaloTag fusion proteins and their seroreactivity analyzed using plasma from CRC patients at stages I-IV (n = 31), individuals with premalignant lesions (n = 31), and healthy individuals (n = 48). p53γ, Δ40p53β, Δ40p53γ, Δ133p53γ, Δ160p53γ, TAp63α, TAp63δ, ΔNp63α, and ΔNp63δ, together with the specific C-terminal end α and δ p63 peptides, were found to be more seroreactive against plasma from CRC patients and/or individuals with premalignant lesions than from healthy individuals. In addition, ROC (receiver operating characteristic) curves revealed a high diagnostic ability of those p53 and p63 proteoforms to detect CRC and premalignant individuals (AUC higher than 85%). Finally, electrochemical biosensing platforms were employed in POC-like devices to investigate their usefulness for CRC detection using selected p53 and p63 proteoforms. Our results demonstrate not only the potential of these biosensors for the simultaneous analysis of proteoforms' seroreactivity, but also their convenience and versatility for the clinical detection of CRC by liquid biopsy. In conclusion, we here show that p53 and p63 proteoforms possess differential seroreactivity in CRC patients in comparison to controls, distinctive from canonical proteins, which should improve the diagnostic panels for obtaining a blood-based biomarker signature for CRC detection.
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Affiliation(s)
- Ana Montero-Calle
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, 28220 Madrid, Spain; (A.M.-C.); (M.G.-A.)
| | - María Garranzo-Asensio
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, 28220 Madrid, Spain; (A.M.-C.); (M.G.-A.)
| | - Rebeca M. Torrente-Rodríguez
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28014 Madrid, Spain; (R.M.T.-R.); (V.R.-V.M.); (J.M.P.); (S.C.)
| | - Víctor Ruiz-Valdepeñas Montiel
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28014 Madrid, Spain; (R.M.T.-R.); (V.R.-V.M.); (J.M.P.); (S.C.)
| | - Carmen Poves
- Gastroenterology Unit, Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain;
| | - Jana Dziaková
- Surgical Digestive Department, Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain
| | - Rodrigo Sanz
- Surgical Digestive Department, Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain
| | - Cristina Díaz del Arco
- Surgical Pathology Department, Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain (M.J.F.-A.)
| | - José Manuel Pingarrón
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28014 Madrid, Spain; (R.M.T.-R.); (V.R.-V.M.); (J.M.P.); (S.C.)
| | | | - Susana Campuzano
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28014 Madrid, Spain; (R.M.T.-R.); (V.R.-V.M.); (J.M.P.); (S.C.)
| | - Rodrigo Barderas
- Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, 28220 Madrid, Spain; (A.M.-C.); (M.G.-A.)
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13
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McGriff A, Placzek WJ. Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families. PLoS One 2023; 18:e0277726. [PMID: 36696417 PMCID: PMC9876281 DOI: 10.1371/journal.pone.0277726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
B-cell lymphoma 2 (Bcl-2) proteins are central, conserved regulators of apoptosis. Bcl-2 family function is regulated by binding interactions between the Bcl-2 homology 3 (BH3) motif in pro-apoptotic family members and the BH3 binding groove found in both the pro-apoptotic effector and anti-apoptotic Bcl-2 family members. A novel motif, the reverse BH3 (rBH3), has been shown to interact with the anti-apoptotic Bcl-2 homolog MCL1 (Myeloid cell leukemia 1) and have been identified in the p53 homolog p73, and the CDK4/6 (cyclin dependent kinase 4/6) inhibitor p18INK4c, (p18, cyclin-dependent kinase 4 inhibitor c). To determine the conservation of rBH3 motif, we first assessed conservation of MCL1's BH3 binding groove, where the motif binds. We then constructed neighbor-joining phylogenetic trees of the INK4 and p53 protein families and analyzed sequence conservation using sequence logos of the rBH3 locus. This showed the rBH3 motif is conserved throughout jawed vertebrates p63 and p73 sequences and in chondrichthyans, amphibians, mammals, and some reptiles in p18. Finally, a potential rBH3 motif was identified in mammalian and osteichthyan p19INK4d (p19, cyclin dependent kinase 4 inhibitor d). These findings demonstrate that the interaction between MCL1 and other cellular proteins mediated by the rBH3 motif may be conserved throughout jawed vertebrates.
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Affiliation(s)
- Anna McGriff
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - William J. Placzek
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
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14
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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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15
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Yu S, Ji G, Zhang L. The role of p53 in liver fibrosis. Front Pharmacol 2022; 13:1057829. [PMID: 36353498 PMCID: PMC9637836 DOI: 10.3389/fphar.2022.1057829] [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: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 08/27/2023] Open
Abstract
The tumor suppressor p53 is the central hub of a molecular network, which controls cell proliferation and death, and also plays an important role in the occurrence and development of liver fibrosis. The abundant post-translational processing and modification endow the functional diversity of p53. Considering the relationship between p53 and liver fibrosis, drug intervention targeting p53 or management of p53 regulation might be effective strategies to treat liver fibrosis. Here, we systematically discuss the regulation of p53 in different liver cells (hepatocytes, immune cells, HSCs, etc) and the role of p53 in the development of liver fibrosis, and propose possible interventions to prevent the pathogenic processes of liver fibrosis.
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Affiliation(s)
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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16
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Distinct interactors define the p63 transcriptional signature in epithelial development or cancer. Biochem J 2022; 479:1375-1392. [PMID: 35748701 PMCID: PMC9250260 DOI: 10.1042/bcj20210737] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022]
Abstract
The TP63 is an indispensable transcription factor for development and homeostasis of epithelia and its derived glandular tissue. It is also involved in female germline cell quality control, muscle and thymus development. It is expressed as multiple isoforms transcribed by two independent promoters, in addition to alternative splicing occurring at the mRNA 3′-UTR. Expression of the TP63 gene, specifically the amino-deleted p63 isoform, ΔNp63, is required to regulate numerous biological activities, including lineage specification, self-renewal capacity of epithelial stem cells, proliferation/expansion of basal keratinocytes, differentiation of stratified epithelia. In cancer, ΔNp63 is implicated in squamous cancers pathogenesis of different origin including skin, head and neck and lung and in sustaining self-renewal of cancer stem cells. How this transcription factor can control such a diverse set of biological pathways is central to the understanding of the molecular mechanisms through which p63 acquires oncogenic activity, profoundly changing its down-stream transcriptional signature. Here, we highlight how different proteins interacting with p63 allow it to regulate the transcription of several central genes. The interacting proteins include transcription factors/regulators, epigenetic modifiers, and post-transcriptional modifiers. Moreover, as p63 depends on its interactome, we discuss the hypothesis to target the protein interactors to directly affect p63 oncogenic activities and p63-related diseases.
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17
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Eustace AJ, Lee MJ, Colley G, Roban J, Downing T, Buchanan PJ. Aberrant calcium signalling downstream of mutations in TP53 and the PI3K/AKT pathway genes promotes disease progression and therapy resistance in triple negative breast cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:560-576. [PMID: 36176752 PMCID: PMC9511797 DOI: 10.20517/cdr.2022.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/04/2022] [Accepted: 05/25/2022] [Indexed: 06/16/2023]
Abstract
Triple-negative breast cancer (TNBC) is characterized as an aggressive form of breast cancer (BC) associated with poor patient outcomes. For the majority of patients, there is a lack of approved targeted therapies. Therefore, chemotherapy remains a key treatment option for these patients, but significant issues around acquired resistance limit its efficacy. Thus, TNBC has an unmet need for new targeted personalized medicine approaches. Calcium (Ca2+) is a ubiquitous second messenger that is known to control a range of key cellular processes by mediating signalling transduction and gene transcription. Changes in Ca2+ through altered calcium channel expression or activity are known to promote tumorigenesis and treatment resistance in a range of cancers including BC. Emerging evidence shows that this is mediated by Ca2+ modulation, supporting the function of tumour suppressor genes (TSGs) and oncogenes. This review provides insight into the underlying alterations in calcium signalling and how it plays a key role in promoting disease progression and therapy resistance in TNBC which harbours mutations in tumour protein p53 (TP53) and the PI3K/AKT pathway.
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Affiliation(s)
- Alex J. Eustace
- DCU Cancer Research, Dublin City University, Dublin D9, Ireland
- National Institute Cellular Biotechnology, Dublin City University, Dublin D9, Ireland
- School of Biotechnology, Dublin City University, Dublin D9, Ireland
| | - Min Jie Lee
- School of Biotechnology, Dublin City University, Dublin D9, Ireland
| | - Grace Colley
- National Institute Cellular Biotechnology, Dublin City University, Dublin D9, Ireland
- School of Biotechnology, Dublin City University, Dublin D9, Ireland
| | - Jack Roban
- School of Biotechnology, Dublin City University, Dublin D9, Ireland
| | - Tim Downing
- DCU Cancer Research, Dublin City University, Dublin D9, Ireland
- School of Biotechnology, Dublin City University, Dublin D9, Ireland
| | - Paul J. Buchanan
- DCU Cancer Research, Dublin City University, Dublin D9, Ireland
- National Institute Cellular Biotechnology, Dublin City University, Dublin D9, Ireland
- School of Nursing, Psychotherapy, and Community Health, Dublin City University, Dublin D9, Ireland
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18
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Nurhayati APD, Rihandoko A, Fadlan A, Ghaissani SS, Jadid N, Setiawan E. Anti-cancer potency by induced apoptosis by molecular docking P53, caspase, cyclin D1, cytotoxicity analysis and phagocytosis activity of trisindoline 1,3 and 4. Saudi Pharm J 2022; 30:1345-1359. [PMID: 36249936 PMCID: PMC9563049 DOI: 10.1016/j.jsps.2022.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 06/17/2022] [Indexed: 11/27/2022] Open
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19
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Moschos SJ, Sandhu S, Lewis KD, Sullivan RJ, Puzanov I, Johnson DB, Henary HA, Wong H, Upreti VV, Long GV, Flaherty KT. Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in Metastatic Melanoma; a phase 1 study. Invest New Drugs 2022; 40:1051-1065. [PMID: 35635631 PMCID: PMC9395504 DOI: 10.1007/s10637-022-01253-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 04/26/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma. METHODS Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232. RESULTS 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively. CONCLUSION The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.
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Affiliation(s)
- Stergios J Moschos
- Department of Medicine, Division of Medical Oncology, The University of North Carolina at Chapel Hill and the Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
| | - Shahneen Sandhu
- Department of Medical Oncology, Peter MaCallum Cancer Center and the University of Melbourne, Melbourne, VIC, Australia
| | - Karl D Lewis
- Division of Medical Oncology, Anschultz Medical Campus, University of Colorado, Denver, CO, USA
| | - Ryan J Sullivan
- Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Igor Puzanov
- Department of Medicine, Vanderbilt University Medical Center and Ingram Cancer Center, Nashville TN, USA
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center and Ingram Cancer Center, Nashville TN, USA
| | | | - Hansen Wong
- Clinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, CA, USA
| | - Vijay V Upreti
- Clinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, CA, USA
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney and Royal North Shore, and Mater Hospitals, Sydney NSW, Australia
| | - Keith T Flaherty
- Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA
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20
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Santos J, Pallarès I, Iglesias V, Ventura S. Cryptic amyloidogenic regions in intrinsically disordered proteins: Function and disease association. Comput Struct Biotechnol J 2021; 19:4192-4206. [PMID: 34527192 PMCID: PMC8349759 DOI: 10.1016/j.csbj.2021.07.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 11/21/2022] Open
Abstract
The amyloid conformation is considered a fundamental state of proteins and the propensity to populate it a generic property of polypeptides. Multiple proteome-wide analyses addressed the presence of amyloidogenic regions in proteins, nurturing our understanding of their nature and biological implications. However, these analyses focused on highly aggregation-prone and hydrophobic stretches that are only marginally found in intrinsically disordered regions (IDRs). Here, we explore the prevalence of cryptic amyloidogenic regions (CARs) of polar nature in IDRs. CARs are widespread in IDRs and associated with IDPs function, with particular involvement in protein–protein interactions, but their presence is also connected to a risk of malfunction. By exploring this function/malfunction dichotomy, we speculate that ancestral CARs might have evolved into functional interacting regions playing a significant role in protein evolution at the origins of life.
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Key Words
- APR, Aggregation-prone region
- Aggregation
- Amyloid
- CARs, Cryptic amyloidogenic regions
- CD, Circular dichroism
- CR, Congo red
- Evolution
- FTIR, Fourier transform infrared
- IDPs, Intrinsically disordered proteins
- IDRs, Intrinsically disordered regions
- Intrinsically disordered proteins
- PBS, Phosphate buffer saline
- PPI, Protein-protein interactions
- Protein disorder
- Protein–protein interactions
- Rb, Retinoblastoma associated proteins
- RbC, Core region of Rb
- TEM, Transmission electron microscopy
- Th-T, Thioflavin-T
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Affiliation(s)
- Jaime Santos
- Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| | - Irantzu Pallarès
- Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| | - Valentín Iglesias
- Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| | - Salvador Ventura
- Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
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21
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Bhat A, Bhat GR, Verma S, Shah R, Nagpal A, Sharma B, Bakshi D, Suri J, Singh S, Tanwar M, Vaishnavi S, Bhat A, Kumar R. Polymorphism in the TP63 gene imparts a potential risk for leukemia in the North Indian population. Afr Health Sci 2021; 21:1243-1249. [PMID: 35222588 PMCID: PMC8843251 DOI: 10.4314/ahs.v21i3.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The role of single nucleotide polymorphism rs10937405 (C>T) of the TP63 gene in cancer including leukemia has previously been studied in different world populations; however, the role of this variant in leukemia in the North Indian population of Jammu and Kashmir is still unknown. OBJECTIVES In the present study, we investigated the association of genetic variant rs10937405 with leukemic in the Jammu and Kashmir population. METHODS A total of 588 subjects, (188 cases and 400 controls) were recruited for the study. The rs10937405 variant was genotyped by using the real-time based TaqMan assay. RESULTS A statistically significant association was observed between the rs10937405 and leukemia [OR of 1.94 (95% CI 1.51-2.48), p=1.2x10-6]. CONCLUSION The current study concludes that the rs10937405 variant is a risk factor for the development of leukemia in the population of Jammu and Kashmir, North India. However, it would be interesting to explore the contribution of this variant in other cancers as well. Our findings will help in the development of diagnostic markers for leukemia in the studied population and potentially for other North Indian populations.
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Affiliation(s)
- Amrita Bhat
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
| | - Gh Rasool Bhat
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
| | - Sonali Verma
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
| | - Ruchi Shah
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
| | - Ashna Nagpal
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
| | - Bhanu Sharma
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
| | - Divya Bakshi
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
| | | | - Supinder Singh
- Department of Medicine, ASCOMS, Sidhra, J&K, India, 182320
| | - Mukesh Tanwar
- Departments of Genetics, Maharishi Dayanand University, Rohtak, Haryana, India
| | | | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, J&K, India
| | - Rakesh Kumar
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India,182320
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22
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Paul D, Komarova NL. Multi-scale network targeting: A holistic systems-biology approach to cancer treatment. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2021; 165:72-79. [PMID: 34428429 DOI: 10.1016/j.pbiomolbio.2021.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 08/05/2021] [Accepted: 08/10/2021] [Indexed: 11/15/2022]
Abstract
The vulnerabilities of cancer at the cellular and, recently, with the introduction of immunotherapy, at the tissue level, have been exploited with variable success. Evaluating the cancer system vulnerabilities at the organismic level through analysis of network topology and network dynamics can potentially predict novel anti-cancer drug targets directed at the macroscopic cancer networks. Theoretical work analyzing the properties and the vulnerabilities of the multi-scale network of cancer needs to go hand-in-hand with experimental research that uncovers the biological nature of the relevant networks and reveals new targetable vulnerabilities. It is our hope that attacking cancer on different spatial scales, in a concerted integrated approach, may present opportunities for novel ways to prevent treatment resistance.
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Affiliation(s)
- Doru Paul
- Medical Oncology, Weill Cornell Medicine, 1305 York Avenue 12th Floor, New York, NY, 10021, USA.
| | - Natalia L Komarova
- Department of Mathematics, University of California Irvine, Irvine, CA, 92697, USA.
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23
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Hernández Borrero LJ, El-Deiry WS. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer 2021; 1876:188556. [PMID: 33932560 PMCID: PMC8730328 DOI: 10.1016/j.bbcan.2021.188556] [Citation(s) in RCA: 295] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022]
Abstract
TP53 is the most commonly mutated gene in human cancer with over 100,000 literature citations in PubMed. This is a heavily studied pathway in cancer biology and oncology with a history that dates back to 1979 when p53 was discovered. The p53 pathway is a complex cellular stress response network with multiple diverse inputs and downstream outputs relevant to its role as a tumor suppressor pathway. While inroads have been made in understanding the biology and signaling in the p53 pathway, the p53 family, transcriptional readouts, and effects of an array of mutants, the pathway remains challenging in the realm of clinical translation. While the role of mutant p53 as a prognostic factor is recognized, the therapeutic modulation of its wild-type or mutant activities remain a work-in-progress. This review covers current knowledge about the biology, signaling mechanisms in the p53 pathway and summarizes advances in therapeutic development.
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Affiliation(s)
- Liz J Hernández Borrero
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, United States of America; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, United States of America; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, United States of America.
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24
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Gomes AS, Ramos H, Inga A, Sousa E, Saraiva L. Structural and Drug Targeting Insights on Mutant p53. Cancers (Basel) 2021; 13:3344. [PMID: 34283062 PMCID: PMC8268744 DOI: 10.3390/cancers13133344] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/29/2021] [Accepted: 06/29/2021] [Indexed: 12/20/2022] Open
Abstract
p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53.
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Affiliation(s)
- Ana Sara Gomes
- LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal; (A.S.G.); (H.R.)
| | - Helena Ramos
- LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal; (A.S.G.); (H.R.)
| | - Alberto Inga
- Laboratory of Transcriptional Networks, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy;
| | - Emília Sousa
- Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
- CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal
| | - Lucília Saraiva
- LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal; (A.S.G.); (H.R.)
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25
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Pawge G, Khatik GL. p53 regulated senescence mechanism and role of its modulators in age-related disorders. Biochem Pharmacol 2021; 190:114651. [PMID: 34118220 DOI: 10.1016/j.bcp.2021.114651] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 10/21/2022]
Abstract
Multiple co-morbidities are associated with age, and there is a need for the broad-spectrum drug to prevent multiple regimens that may cause an adverse effect in the geriatric population. Cellular senescence is a primary mechanism for ageing in various tissues. p53, a tumor suppressor protein, plays a significant role in forming DNA damage foci and post different stress responses. DNA damage foci can be transient or persistent that can progress to DNA-SCARS inducing senescence. p53 also plays a role in apoptosis and negative regulation of SASP. Few upstream targets like FOXO4, MDM2, MDM4, USP7 control the availability of p53 for apoptosis. Hence, the senolytic therapies, modulating p53 upstream targets, can be a good approach for preventing age-related disorders. This review discusses the insights on the role of p53 in the formation of DNA-SCARS, various upstream target proteins, and pathways involved in p53 regulation. Further, the review aimed to include recently discovered small molecules acting on these upstream targets, and those can be modified using medicinal chemistry approaches to give successful senotherapeutics.
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Affiliation(s)
- Girija Pawge
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research- Raebareli, New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226301, India
| | - Gopal L Khatik
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research- Raebareli, New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226301, India.
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26
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Cadena-Cruz JE, Guamán-Ortiz LM, Romero-Benavides JC, Bailon-Moscoso N, Murillo-Sotomayor KE, Ortiz-Guamán NV, Heredia-Moya J. Synthesis of 4,4'-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) and evaluation of their antioxidant and anticancer activities. BMC Chem 2021; 15:38. [PMID: 34082794 PMCID: PMC8176600 DOI: 10.1186/s13065-021-00765-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023] Open
Abstract
Background Pyrazoles have attracted particular attention due to the diverse biological activities associated with this heterocyclic system, and some have been shown to be cytotoxic to several human cell lines. Several drugs currently on the market have this heterocycle as the key structural motif, and some have been approved for the treatment of different types of cancer. Results 4,4ʹ-(Arylmethylene)bis(1H-pyrazol-5-ols) derivatives 3a–q were synthetized by a three components reaction of 3-methyl-1-phenyl-5-pyrazolone (1) with various benzaldehydes 2 catalyzed by sodium acetate at room temperature. The structures of all synthesized compounds were characterized by physicochemical properties and spectral means (IR and NMR) and were evaluated for their radical scavenging activity by DPPH assay and tested in vitro on colorectal RKO carcinoma cells in order to determine their cytotoxic properties. All 4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives 3a–q were synthetized in high to excellent yield, and pure products were isolated by simple filtration. All compounds have good radical scavenging activity, and half of them are more active than ascorbic acid used as standard. Conclusion Several derivatives proved to be cytotoxic in the RKO cell line. In particular, compound 3i proved to be a very potent scavenger with an IC50 of 6.2 ± 0.6 µM and exhibited an IC50 of 9.9 ± 1.1 μM against RKO cell. Autophagy proteins were activated as a survival mechanism, whereas the predominant pathway of death was p53-mediated apoptosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13065-021-00765-y.
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Affiliation(s)
| | - Luis M Guamán-Ortiz
- Departamento de Ciencias de La Salud, Universidad Técnica Particular de Loja, San Cayetano Alto s/n, C.P. 11 01 608, Loja, Ecuador
| | - Juan Carlos Romero-Benavides
- Departamento de Química y Ciencias Exactas, Universidad Técnica Particular de Loja, San Cayetano Alto s/n, C.P. 11 01 608, Loja, Ecuador
| | - Natalia Bailon-Moscoso
- Departamento de Ciencias de La Salud, Universidad Técnica Particular de Loja, San Cayetano Alto s/n, C.P. 11 01 608, Loja, Ecuador
| | - Kevin E Murillo-Sotomayor
- Departamento de Ciencias de La Salud, Universidad Técnica Particular de Loja, San Cayetano Alto s/n, C.P. 11 01 608, Loja, Ecuador
| | - Nadia V Ortiz-Guamán
- Departamento de Ciencias de La Salud, Universidad Técnica Particular de Loja, San Cayetano Alto s/n, C.P. 11 01 608, Loja, Ecuador
| | - Jorge Heredia-Moya
- Centro de Investigación Biomédica (CENBIO), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, 170527, Quito, Ecuador.
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Mishra S, Charan M, Verma AK, Ramaswamy B, Ahirwar DK, Ganju RK. Racially Disparate Expression of mTOR/ERK-1/2 Allied Proteins in Cancer. Front Cell Dev Biol 2021; 9:601929. [PMID: 33996789 PMCID: PMC8120233 DOI: 10.3389/fcell.2021.601929] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
Recent studies revealed that ethnic differences in mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK-1/2) signaling pathways might be associated with the development and progression of different human malignancies. The African American (AA) population has an increased rate of cancer incidence and mortality compared to the Caucasian American (CA) population. Although the socioeconomic differences across different ethnic groups contribute to the disparity in developing different cancers, recent scientific evidence indicates the association of molecular and genetic variations in racial disparities of different human malignancies. The mTOR and ERK-1/2 signaling pathways are one of the well-known oncogenic signaling mechanisms that regulate diverse molecular and phenotypic aspects of normal as well as cancer cells in response to different external or internal stimuli. To date, very few studies have been carried out to explore the significance of racial disparity with abnormal mTOR and ERK-1/2 kinase signaling pathways, which may contribute to the development of aggressive human cancers. In this review, we discuss the differential regulation of mTOR and ERK-1/2 kinase signaling pathways across different ethnic groups, especially between AA and CA populations. Notably, we observed that key signaling proteins associated with mTOR and ERK-1/2 pathway including transforming growth factor-beta (TGF-β), Akt, and VEGFR showed racially disparate expression in cancer patients. Overall, this review article encompasses the significance of racially disparate signaling molecules related to mTOR/ERK1/2 and their potential in developing tailor-made anti-cancer therapies.
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Affiliation(s)
- Sanjay Mishra
- Department of Pathology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Manish Charan
- Department of Pathology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Ajeet Kumar Verma
- Department of Pathology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH, United States
| | | | - Dinesh Kumar Ahirwar
- Department of Pathology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Ramesh K Ganju
- Department of Pathology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH, United States.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
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Łukasik P, Załuski M, Gutowska I. Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review. Int J Mol Sci 2021; 22:ijms22062935. [PMID: 33805800 PMCID: PMC7998717 DOI: 10.3390/ijms22062935] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
Cyclin-dependent kinases (CDKs) are involved in many crucial processes, such as cell cycle and transcription, as well as communication, metabolism, and apoptosis. The kinases are organized in a pathway to ensure that, during cell division, each cell accurately replicates its DNA, and ensure its segregation equally between the two daughter cells. Deregulation of any of the stages of the cell cycle or transcription leads to apoptosis but, if uncorrected, can result in a series of diseases, such as cancer, neurodegenerative diseases (Alzheimer’s or Parkinson’s disease), and stroke. This review presents the current state of knowledge about the characteristics of cyclin-dependent kinases as potential pharmacological targets.
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Affiliation(s)
- Paweł Łukasik
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Michał Załuski
- Department of Pharmaceutical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland;
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland;
- Correspondence:
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29
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Evaluating the Influence of a G-Quadruplex Prone Sequence on the Transactivation Potential by Wild-Type and/or Mutant P53 Family Proteins through a Yeast-Based Functional Assay. Genes (Basel) 2021; 12:genes12020277. [PMID: 33672023 PMCID: PMC7919268 DOI: 10.3390/genes12020277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 02/06/2023] Open
Abstract
P53, P63, and P73 proteins belong to the P53 family of transcription factors, sharing a common gene organization that, from the P1 and P2 promoters, produces two groups of mRNAs encoding proteins with different N-terminal regions; moreover, alternative splicing events at C-terminus further contribute to the generation of multiple isoforms. P53 family proteins can influence a plethora of cellular pathways mainly through the direct binding to specific DNA sequences known as response elements (REs), and the transactivation of the corresponding target genes. However, the transcriptional activation by P53 family members can be regulated at multiple levels, including the DNA topology at responsive promoters. Here, by using a yeast-based functional assay, we evaluated the influence that a G-quadruplex (G4) prone sequence adjacent to the p53 RE derived from the apoptotic PUMA target gene can exert on the transactivation potential of full-length and N-terminal truncated P53 family α isoforms (wild-type and mutant). Our results show that the presence of a G4 prone sequence upstream or downstream of the P53 RE leads to significant changes in the relative activity of P53 family proteins, emphasizing the potential role of structural DNA features as modifiers of P53 family functions at target promoter sites.
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dos Santos GA, Reis ST, Leite KRM, Srougi M. Telomere Attrition and p53 Response 1 (TAPR1): a new player in cancer biology? Clinics (Sao Paulo) 2021; 76:e2997. [PMID: 34133663 PMCID: PMC8158669 DOI: 10.6061/clinics/2021/e2997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Affiliation(s)
- Gabriel Arantes dos Santos
- Laboratorio de Investigacao Medica (LIM55), Departamento de Urologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Instituto D'Or de Pesquisa e Ensino (IDOR), Sao Paulo, SP, BR
- Corresponding author. E-mail:
| | - Sabrina T. Reis
- Laboratorio de Investigacao Medica (LIM55), Departamento de Urologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Centro Universitario Atenas (UniAtenas), Passos, MG, BR
- Universidade do Estado de Minas Gerais (UEMG), Passos, MG, BR
| | - Katia Ramos Moreira Leite
- Laboratorio de Investigacao Medica (LIM55), Departamento de Urologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Miguel Srougi
- Laboratorio de Investigacao Medica (LIM55), Departamento de Urologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Instituto D'Or de Pesquisa e Ensino (IDOR), Sao Paulo, SP, BR
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p73: From the p53 shadow to a major pharmacological target in anticancer therapy. Pharmacol Res 2020; 162:105245. [PMID: 33069756 DOI: 10.1016/j.phrs.2020.105245] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 02/06/2023]
Abstract
p73, along with p53 and p63, belongs to the p53 family of transcription factors. Besides the p53-like tumor suppressive activities, p73 has unique roles, namely in neuronal development and differentiation. In addition, the TP73 gene is rarely mutated in tumors. This makes p73 a highly appealing therapeutic target, particularly towards cancers with a null or disrupted p53 pathway. Distinct isoforms are transcribed from the TP73 locus either with (TAp73) and without (ΔNp73) the N-terminal transactivation domain. Conversely to TA tumor suppressors, ΔN proteins exhibit oncogenic properties by inhibiting p53 and TA protein functions. As such, p73 isoforms compose a puzzled and challenging regulatory pathway. This state-of-the-art review affords an update overview on p73 structure, biological functions and pharmacological regulation. Importantly, it addresses the relevance of p73 isoforms in carcinogenesis, highlighting their potential as drug targets in anticancer therapy. A critical discussion of major pharmacological approaches to promote p73 tumor suppressive activities, with relevant survival outcomes for cancer patients, is also provided.
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32
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Loureiro JB, Abrantes M, Oliveira PA, Saraiva L. P53 in skin cancer: From a master player to a privileged target for prevention and therapy. Biochim Biophys Acta Rev Cancer 2020; 1874:188438. [PMID: 32980466 DOI: 10.1016/j.bbcan.2020.188438] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
The increasing incidence of skin cancer (SC) is a global health concern. The commonly reported side effects and resistance mechanisms have imposed the pursuit for new therapeutic alternatives. Moreover, additional preventive strategies should be adopted to strengthen prevention and reduce the rising number of newly SC cases. This review provides relevant insights on the role of p53 tumour suppressor protein in melanoma and non-melanoma skin carcinogenesis, also highlighting the therapeutic potential of p53-targeting drugs against SC. In fact, several evidences are provided demonstrating the encouraging outcomes achieved with p53-activating drugs, alone and in combination with currently available therapies in SC. Another pertinent perspective falls on targeting p53 mutations, as molecular signatures in premature phases of photocarcinogenesis, in future SC preventive approaches. Overall, this review affords a critical and timely discussion of relevant issues related to SC prevention and therapy. Importantly, it paves the way to future studies that may boost the clinical translation of p53-activating agents, making them new effective alternatives in precision medicine of SC therapy and prevention.
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Affiliation(s)
- J B Loureiro
- LAQV/REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - M Abrantes
- Biophysics Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI Consortium/Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
| | - P A Oliveira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - L Saraiva
- LAQV/REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
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Eskandari M, Shi Y, Liu J, Albanese J, Goel S, Verma A, Wang Y. The expression of MDM2, MDM4, p53 and p21 in myeloid neoplasms and the effect of MDM2/MDM4 dual inhibitor. Leuk Lymphoma 2020; 62:167-175. [PMID: 32924682 DOI: 10.1080/10428194.2020.1817441] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
p53 together with its downstream product p21 plays an important role in tumorigenesis development. MDM2 and MDM4 are two p53 regulators. We studied the expression of p53, p21, MDM2, and MDM4 in a total of 120 cases of myeloid neoplasms including MDS, AML or MDS/MPN, and control, using single and double immunohistochemical stains. We found TP53 mutations had a worse outcome in patients with AML/MDS, and p53 expression detected by immunohistochemistry had a similar prognostic value. p21 expression was strongly related to TP53 mutation status, with loss of expression in almost all TP53 mutated cases. MDM2 and MDM4 were highly expressed in hematopoietic cells in both benign and neoplastic cells. MDM2/p53 double positive cells exceeded MDM4/p53 double positive cells in neoplastic cases. Finally, we observed that p21 protein expression was up regulated upon the use of ALRN-6924 (Aileron) while no significant changes were seen in p53, MDM2 and MDM4 expression.
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Affiliation(s)
| | - Yang Shi
- Department of Pathology, Montefiore Medical Center, New York, NY, USA
| | - John Liu
- Rensselaer Polytechnic Institute, Troy, MI, USA
| | - Joseph Albanese
- Department of Pathology, Montefiore Medical Center, New York, NY, USA
| | - Swati Goel
- Department of Oncology, Montefiore Einstein Center for Cancer Care, New York, NY, USA
| | - Amit Verma
- Department of Oncology, Montefiore Einstein Center for Cancer Care, New York, NY, USA
| | - Yanhua Wang
- Department of Pathology, Montefiore Medical Center, New York, NY, USA
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34
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Zanjirband M, Rahgozar S. Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed. Curr Drug Targets 2020; 20:1091-1111. [PMID: 30947669 DOI: 10.2174/1389450120666190402120701] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 12/16/2022]
Abstract
MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.
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Affiliation(s)
- Maryam Zanjirband
- Department of Cellular and Molecular Biology, Faculty of Science, University of Isfahan, Azadi Square, Isfahan, Iran
| | - Soheila Rahgozar
- Department of Cellular and Molecular Biology, Faculty of Science, University of Isfahan, Azadi Square, Isfahan, Iran
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35
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Tan YS, Mhoumadi Y, Verma CS. Roles of computational modelling in understanding p53 structure, biology, and its therapeutic targeting. J Mol Cell Biol 2020; 11:306-316. [PMID: 30726928 PMCID: PMC6487789 DOI: 10.1093/jmcb/mjz009] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/14/2018] [Accepted: 01/31/2019] [Indexed: 12/21/2022] Open
Abstract
The transcription factor p53 plays pivotal roles in numerous biological processes, including the suppression of tumours. The rich availability of biophysical data aimed at understanding its structure–function relationships since the 1990s has enabled the application of a variety of computational modelling techniques towards the establishment of mechanistic models. Together they have provided deep insights into the structure, mechanics, energetics, and dynamics of p53. In parallel, the observation that mutations in p53 or changes in its associated pathways characterize several human cancers has resulted in a race to develop therapeutic modulators of p53, some of which have entered clinical trials. This review describes how computational modelling has played key roles in understanding structural-dynamic aspects of p53, formulating hypotheses about domains that are beyond current experimental investigations, and the development of therapeutic molecules that target the p53 pathway.
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Affiliation(s)
- Yaw Sing Tan
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore
| | - Yasmina Mhoumadi
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore.,School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore
| | - Chandra S Verma
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore.,School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore.,Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore
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36
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Li W, Zhang W, Zhang J. A Novel Model Integration Network Inference Algorithm with Clustering and Hub Genes Finding. Mol Inform 2020; 39:e1900075. [DOI: 10.1002/minf.201900075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 01/14/2020] [Indexed: 11/08/2022]
Affiliation(s)
- Wenchao Li
- State Key Laboratory of Industrial Control TechnologyInstitute of Cyber-Systems and Control of Zhejiang University Hangzhou China
| | - Wei Zhang
- State Key Laboratory of Industrial Control TechnologyInstitute of Cyber-Systems and Control of Zhejiang University Hangzhou China
| | - Jianming Zhang
- State Key Laboratory of Industrial Control TechnologyInstitute of Cyber-Systems and Control of Zhejiang University Hangzhou China
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37
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Fujiyama H, Tsuji T, Hironaka K, Yoshida K, Sugimoto N, Fujita M. GRWD1 directly interacts with p53 and negatively regulates p53 transcriptional activity. J Biochem 2020; 167:15-24. [PMID: 31545368 DOI: 10.1093/jb/mvz075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 09/11/2019] [Indexed: 12/15/2022] Open
Abstract
Glutamate-rich WD40 repeat containing 1 (GRWD1) functions as a histone chaperone to promote loading of the MCM replication helicase at replication origins. GRWD1 is overexpressed in several cancer cell lines, and GRWD1 overexpression confers tumorigenic potential in human cells. However, less is known concerning its oncogenic activity. Our previous analysis showed that GRWD1 negatively regulates the tumour suppressor p53 via the RPL11-MDM2-p53 and RPL23-MDM2-p53 axes. Here, we demonstrate that GRWD1 directly interacts with p53 via the p53 DNA-binding domain. Upon DNA damage, GRWD1 downregulation resulted in increased p21 expression. Conversely, GRWD1 co-expression suppressed several p53-regulated promoters. GRWD1 interacted with the p21 and MDM2 promoters, and these interactions required p53. By using the Human Cancer Genome Atlas database, we found that GRWD1 expression levels are inversely correlated with the expression levels of some p53-target genes. Interestingly, high GRWD1 expression in combination with low expression levels of some p53-target genes was significantly correlated with poor prognosis in skin melanoma patients with wild-type p53. Taken together, our findings suggest a novel oncogenic function of GRWD1 as a transcriptional regulator of p53 and that GRWD1 might be an attractive therapeutic target and prognostic marker in cancer therapy.
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Affiliation(s)
- Hiroki Fujiyama
- Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
| | - Takahiro Tsuji
- Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
| | - Kensuke Hironaka
- Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
| | - Kazumasa Yoshida
- Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
| | - Nozomi Sugimoto
- Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
| | - Masatoshi Fujita
- Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
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38
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Sulaimanov N, Kumar S, Burdet F, Ibberson M, Pagni M, Koeppl H. Inferring gene expression networks with hubs using a degree weighted Lasso approach. Bioinformatics 2019; 35:987-994. [PMID: 30165436 DOI: 10.1093/bioinformatics/bty716] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 06/08/2018] [Accepted: 08/25/2018] [Indexed: 11/14/2022] Open
Abstract
MOTIVATION Genome-scale gene networks contain regulatory genes called hubs that have many interaction partners. These genes usually play an essential role in gene regulation and cellular processes. Despite recent advancements in high-throughput technology, inferring gene networks with hub genes from high-dimensional data still remains a challenging problem. Novel statistical network inference methods are needed for efficient and accurate reconstruction of hub networks from high-dimensional data. RESULTS To address this challenge we propose DW-Lasso, a degree weighted Lasso (least absolute shrinkage and selection operator) method which infers gene networks with hubs efficiently under the low sample size setting. Our network reconstruction approach is formulated as a two stage procedure: first, the degree of networks is estimated iteratively, and second, the gene regulatory network is reconstructed using degree information. A useful property of the proposed method is that it naturally favors the accumulation of neighbors around hub genes and thereby helps in accurate modeling of the high-throughput data under the assumption that the underlying network exhibits hub structure. In a simulation study, we demonstrate good predictive performance of the proposed method in comparison to traditional Lasso type methods in inferring hub and scale-free graphs. We show the effectiveness of our method in an application to microarray data of Escherichia coli and RNA sequencing data of Kidney Clear Cell Carcinoma from The Cancer Genome Atlas datasets. AVAILABILITY AND IMPLEMENTATION Under the GNU General Public Licence at https://cran.r-project.org/package=DWLasso. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Nurgazy Sulaimanov
- Department of Electrical Engineering and Information Technology, Technische Universität Darmstadt, Darmstadt, Germany.,Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | - Sunil Kumar
- Department of Electrical Engineering and Information Technology, Technische Universität Darmstadt, Darmstadt, Germany.,Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | | | - Mark Ibberson
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Marco Pagni
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Heinz Koeppl
- Department of Electrical Engineering and Information Technology, Technische Universität Darmstadt, Darmstadt, Germany.,Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
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39
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Alzate JM, Montoya-Florez LM, Pérez JE, Rocha NS, Pedraza-Ordonez FJ. The role of the multi-drug resistance 1, p53, b cell lymphoma 2, and bcl 2-associated X genes in the biologic behavior and chemotherapeutic resistance of canine transmissible venereal tumors. Vet Clin Pathol 2019; 48:730-739. [PMID: 31777108 DOI: 10.1111/vcp.12805] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 02/02/2019] [Accepted: 02/16/2019] [Indexed: 11/27/2022]
Abstract
BACKGROUND Canine transmissible venereal tumors (CTVTs) generally have different cytomorphologic subtypes and phases of progression. Some tumors have variable biologic behavior including a progressive increase in tumor aggressiveness and variable responses to chemotherapy. This behavior is partially due to high p-glycoprotein expression by tumor cells, which leads to the expulsion of chemotherapeutic drugs. Other possible causes include changes in pro- and anti-apoptotic genes from the BCL-2 family and DNA repair systems, which are associated with the p53 gene family. OBJECTIVES We aimed to determine the relative expression of the multi-drug resistance 1 (MDR1), p53, b-cell lymphoma 2 (BCL2), and bcl 2-associated X (BAX) genes in CTVT before and after therapy and establish a relationship with treatment responses, cytomorphologic patterns, and tumor progression identified with histopathology. METHODS RT-qPCR was performed on 21 CTVT tumor samples before and after initiating chemotherapy to determine specific gene expression. Normal canine testicular tissue was used as a negative control for all experiments. RESULTS MDR1 expression was decreased before and after initiating vincristine therapy in CTVT tumor tissues compared with normal canine testicular tissue; p53 and BAX were overexpressed at both time points compared with normal tissue, and no statistical differences were seen between the different morphologic types. However, BAX expression was decreased in the group with quick therapeutic responses but was still overexpressed compared with normal testicular tissue. In the group with the slowest chemotherapeutic responses, BCL2 was overexpressed. CONCLUSION The findings of this study showed a relative increase in MDR1 gene expression in response to chemotherapy and higher expression in plasmacytoid CTVTs compared with the other cytomorphologic patterns. BCL2 overexpression was related to a favorable prognosis, and p53, BAX, and BCL2 were expressed independent of the cytomorphologic CTVT type. All of the genes were expressed independent of tumor progression, as noted on histopathology.
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Affiliation(s)
- Juliana M Alzate
- Faculty of Agricultural Sciences, Veterinary Medicine Department, Universidad de Pamplona, Pamplona, Colombia
| | - Luis M Montoya-Florez
- Faculty of Veterinary Medicine, Universidad Nacional de Colombia, Bogotá, Colombia.,Research Group in Veterinary Medicine and Husbandry - GIDIMEVETZ, Pedagogical and Technological University of Colombia, Tunja, Colombia
| | - Jorge E Pérez
- Basic Sciences Department, Universidad de Caldas, Manizales, Colombia
| | - Noeme S Rocha
- Laboratory of Investigative and Comparative Pathology, FMVZ-UNESP, Botucatu, Brazil
| | - Francisco J Pedraza-Ordonez
- Research Group in Veterinary Pathology, Animal Health Department, Universidad de Caldas, Manizales, Colombia
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40
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Garranzo-Asensio M, Guzmán-Aránguez A, Povés C, Fernández-Aceñero MJ, Montero-Calle A, Ceron MÁ, Fernandez-Diez S, Rodríguez N, Gómez de Cedrón M, Ramírez de Molina A, Domínguez G, Barderas R. The specific seroreactivity to ∆Np73 isoforms shows higher diagnostic ability in colorectal cancer patients than the canonical p73 protein. Sci Rep 2019; 9:13547. [PMID: 31537884 PMCID: PMC6753153 DOI: 10.1038/s41598-019-49960-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 08/31/2019] [Indexed: 02/05/2023] Open
Abstract
The p53-family is tightly regulated at transcriptional level. Due to alternative splicing, up to 40 different theoretical proteoforms have been described for p73 and at least 20 and 10 for p53 and p63, respectively. However, only the canonical proteins have been evaluated as autoantibody targets in cancer patients for diagnosis. In this study, we have cloned and expressed in vitro the most upregulated proteoforms of p73, ΔNp73α and ΔNp73β, for the analysis of their seroreactivity by a developed luminescence based immunoassay test using 145 individual plasma from colorectal cancer, premalignant individuals and healthy controls. ∆Np73α seroreactivity showed the highest diagnostic ability to discriminate between groups. The combination of ∆Np73α, ∆Np73β and p73 proteoforms seroreactivity were able to improve their individual diagnostic ability. Competitive inhibition experiments further demonstrated the presence of unique specific epitopes in ΔNp73 isoforms not present in p73, with several colorectal patients showing unique and specific seroreactivity to the ΔNp73 proteoforms. Overall, we have increased the complexity of the humoral immune response to the p53-family in cancer patients, showing that the proteoforms derived from the alternative splicing of p73 possess a higher diagnostic ability than the canonical protein, which might be extensive for p53 and p63 proteins.
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Affiliation(s)
- María Garranzo-Asensio
- Departamento de Bioquímica y Biología Molecular, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, E-28040, Madrid, Spain
- UFIEC, Chronic Disease Programme, Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain
| | - Ana Guzmán-Aránguez
- Departamento de Bioquímica y Biología Molecular, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, E-28040, Madrid, Spain
| | - Carmen Povés
- Gastroenterology Unit, Hospital Universitario Clínico San Carlos, E-28040, Madrid, Spain
| | | | - Ana Montero-Calle
- UFIEC, Chronic Disease Programme, Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain
| | - María Ángeles Ceron
- Surgical Pathology Department, Hospital Universitario Clínico San Carlos, E-28040, Madrid, Spain
| | | | - Nuria Rodríguez
- Medical Oncology Department, Hospital Universitario La Paz, E-28046, Madrid, Spain
| | - Marta Gómez de Cedrón
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA-FOOD, E-28049, Madrid, Spain
| | - Ana Ramírez de Molina
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA-FOOD, E-28049, Madrid, Spain
| | - Gemma Domínguez
- Departamento de Medicina, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, E-28029, Madrid, Spain.
| | - Rodrigo Barderas
- UFIEC, Chronic Disease Programme, Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain.
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41
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Tiwari S, Dwivedi UN. Discovering Innovative Drugs Targeting Both Cancer and Cardiovascular Disease by Shared Protein-Protein Interaction Network Analyses. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 23:417-425. [PMID: 31329050 DOI: 10.1089/omi.2019.0095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cancer and cardiovascular disease (CVD) have a common co-occurrence. Both diseases display overlapping pathophysiology and risk factors, suggesting shared biological mechanisms. Conditions such as obesity, diabetes, hypertension, smoking, poor diet, and inadequate physical activity can cause both heart disease and cancer. The burgeoning field of onco-cardiology aims to develop diagnostics and innovative therapeutics for both diseases through targeting shared mechanisms and molecular targets. In this overarching context, this expert review presents an analysis of the protein-protein interaction (PPI) networks for onco-cardiology drug discovery. Several PPI complexes such as MDM2-TP53 and CDK4-pRB have been studied for their tumor-suppressive functions. In addition, XIAP-SMAC, RAC1-GEF, Sur-2ESX, and TP53-BRCA1 are other PPI complexes that offer potential breakthrough for onco-cardiology therapeutics innovation. As both cancer and CVD share biological mechanisms to a certain degree, the PPI network analyses for onco-cardiology drug discovery are promising for addressing comorbid diseases in the spirit of systems medicine. We discuss the emerging architecture of PPI networks in cancer and CVD and prospects and challenges for their exploitation toward therapeutics applications. Finally, we emphasize that PPIs that were once thought to be undruggable have become potential new class of innovative drug targets.
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Affiliation(s)
- Sameeksha Tiwari
- Bioinformatics Infrastructure Facility, Department of Biochemistry, Centre of Excellence in Bioinformatics, University of Lucknow, Lucknow, Uttar Pradesh, India
| | - Upendra N Dwivedi
- Bioinformatics Infrastructure Facility, Department of Biochemistry, Centre of Excellence in Bioinformatics, University of Lucknow, Lucknow, Uttar Pradesh, India.,Institute for Development of Advanced Computing, ONGC Centre for Advanced Studies, University of Lucknow, Lucknow, Uttar Pradesh, India
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42
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Ser46 phosphorylation of p53 is an essential event in prolyl-isomerase Pin1-mediated p53-independent apoptosis in response to heat stress. Cell Death Dis 2019; 10:96. [PMID: 30718466 PMCID: PMC6362080 DOI: 10.1038/s41419-019-1316-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 12/02/2018] [Accepted: 01/04/2019] [Indexed: 12/31/2022]
Abstract
Heat stroke has increased in frequency worldwide in recent years and continues to have a high morbidity and mortality. Identification of the mechanisms mediating heat stoke is important and necessary. Our preliminary study revealed heat stress (HS)-induced apoptosis of vascular endothelial cells was associated with reactive oxygen species (ROS)-induced p53 translocation into mitochondria. Previous studies have suggested the prolyl-isomerase Pin1 regulates p53 functioning through specific binding to p53 phosphorylation sites. Based on these studies, we presumed Pin1 is a key intermediate in regulation of mitochondrial p53 translocation through a HS-induced ROS-p53 transcription-independent apoptosis pathway. In this context, we revealed p53 had a crucial role in a HS-induced mitochondrial apoptotic pathway, where p53 protein rapidly translocated into mitochondria in endothelial cells both in vitro and in vivo. In particular, HS caused an increase in p53 phosphorylation at Ser46 that facilitated interactions with phosphorylation-dependent prolyl-isomerase Pin1, which has a key role in promoting HS-induced localization of p53 to mitochondria. Furthermore, we also found ROS production was a critical mediator in HS-induced Pin1/p53 signaling and was involved in regulating mitochondrial apoptosis pathway activation. Therefore, we have contributed to our profound understanding of the mechanism underlying HS-induced endothelial dysfunction in an effort to reduce the mortality and morbidity of heat stroke.
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43
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Cai BH, Wu PH, Chou CK, Huang HC, Chao CC, Chung HY, Lee HY, Chen JY, Kannagi R. Synergistic activation of the NEU4 promoter by p73 and AP2 in colon cancer cells. Sci Rep 2019; 9:950. [PMID: 30700826 PMCID: PMC6353964 DOI: 10.1038/s41598-018-37521-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/07/2018] [Indexed: 12/22/2022] Open
Abstract
More than 50% of colon cancers bear mutations in p53, one of the most important tumor suppressors, and its family members p63 or p73 are expected to contribute to inhibiting the progression of colon cancers. The AP2 family also acts as a tumor suppressor. Here we found that p73 and AP2 are able to activate NEU4, a neuraminidase gene, which removes the terminal sialic acid residues from cancer-associated glycans. Under serum starvation, NEU4 was up-regulated and one of the NEU4 target glycans, sialyl Lewis X, was decreased, whereas p73 and AP2 were up-regulated. Sialyl Lewis X levels were not, however, decreased under starvation conditions in p73- or AP2-knockdown cells. p53 and AP2 underwent protein-protein interactions, exerting synergistic effects to activate p21, and interaction of p53 with AP2 was lost in cells expressing the L350P mutation of p53. The homologous residues in p63 and p73 are L423 and L377, respectively. The synergistic effect of p53/p63 with AP2 to activate genes was lost with the L350P/L423P mutation in p53/p63, but p73 bearing the L377P mutation was able to interact with AP2 and exerted its normal synergistic effects. We propose that p73 and AP2 synergistically activate the NEU4 promoter in colon cancer cells.
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Affiliation(s)
- Bi-He Cai
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. .,Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
| | - Po-Han Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chi-Kan Chou
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hsiang-Chi Huang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
| | - Chia-Chun Chao
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hsiao-Yu Chung
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hsueh-Yi Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jang-Yi Chen
- Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan
| | - Reiji Kannagi
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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44
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Krivtsova O, Makarova A, Lazarevich N. Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma. World J Hepatol 2018; 10:645-661. [PMID: 30386458 PMCID: PMC6206146 DOI: 10.4254/wjh.v10.i10.645] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/08/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors (TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.
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Affiliation(s)
- Olga Krivtsova
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
- M. V. Lomonosov Moscow State University, Moscow 119991, Russian
| | - Anna Makarova
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
| | - Natalia Lazarevich
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
- M. V. Lomonosov Moscow State University, Moscow 119991, Russian
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45
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Stefaniak J, Lewis AM, Conole D, Galan SRG, Bataille CJR, Wynne GM, Castaldi MP, Lundbäck T, Russell AJ, Huber KVM. Chemical Instability and Promiscuity of Arylmethylidenepyrazolinone-Based MDMX Inhibitors. ACS Chem Biol 2018; 13:2849-2854. [PMID: 30216042 PMCID: PMC6198280 DOI: 10.1021/acschembio.8b00665] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Targeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is still limited. The arylmethylidenepyrazolinone SJ-172550 has been reported as a selective MDMX antagonist; yet, uncertainties about its mechanism of action have raised doubts about its use as a chemical probe. Here, we show that, in addition to its unclear mode of action, SJ-172550 is unstable in aqueous buffers, giving rise to side products of unknown biological activity. Using an SJ-172550-derived affinity probe, we observed promiscuous binding to cellular proteins whereas cellular thermal shift assays did not reveal a stabilizing effect on MDMX. Overall, our results raise further questions about the interpretation of data using SJ-172550 and related compounds to investigate cellular phenotypes.
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Affiliation(s)
- Jakub Stefaniak
- Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
| | - Andrew M. Lewis
- Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Daniel Conole
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
| | - Sébastien R. G. Galan
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
| | - Carole J. R. Bataille
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
| | - Graham M. Wynne
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - M. Paola Castaldi
- Discovery Sciences, IMED Biotech Unit, AstraZeneca, Waltham, Massachusetts 02451, United States
| | - Thomas Lundbäck
- Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Angela J. Russell
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Kilian V. M. Huber
- Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Pan Y, Li P, Jia R, Wang M, Yin Z, Cheng A. Regulation of Apoptosis During Porcine Circovirus Type 2 Infection. Front Microbiol 2018; 9:2086. [PMID: 30233552 PMCID: PMC6131304 DOI: 10.3389/fmicb.2018.02086] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 08/15/2018] [Indexed: 12/19/2022] Open
Abstract
Apoptosis, an indispensable innate immune mechanism, regulates cellular homeostasis by removing unnecessary or damaged cells. It contains three signaling pathways: the mitochondria-mediated pathway, the death receptor pathway and the endoplasmic reticulum pathway. The importance of apoptosis in host defenses is stressed by the observation that multiple viruses have evolved various strategies to inhibit apoptosis, thereby blunting the host immune responses and promoting viral propagation. Porcine Circovirus type 2 (PCV2) utilizes various strategies to induce or inhibit programmed cell death. In this article, we review the latest research progress of the apoptosis mechanisms during infection with PCV2, including several proteins of PCV2 regulate apoptosis via interacting with host proteins and multiple signaling pathways involved in PCV2-induced apoptosis, which provides scientific basis for the pathogenesis and prevention of PCV2.
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Affiliation(s)
- Yuhong Pan
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Pengfei Li
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Zhongqiong Yin
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
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Jazvinšćak Jembrek M, Slade N, Hof PR, Šimić G. The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease. Prog Neurobiol 2018; 168:104-127. [DOI: 10.1016/j.pneurobio.2018.05.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 03/04/2018] [Accepted: 05/01/2018] [Indexed: 12/24/2022]
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Alaee M, Nool K, Pasdar M. Plakoglobin restores tumor suppressor activity of p53 R175H mutant by sequestering the oncogenic potential of β-catenin. Cancer Sci 2018; 109:1876-1888. [PMID: 29660231 PMCID: PMC5989865 DOI: 10.1111/cas.13612] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 04/03/2018] [Accepted: 04/06/2018] [Indexed: 12/16/2022] Open
Abstract
Tumor suppressor/transcription factor p53 is mutated in over 50% of all cancers. Some mutant p53 proteins have not only lost tumor suppressor activities but they also gain oncogenic functions (GOF). One of the most frequently expressed GOF p53 mutants is Arg175His (p53R175H ) with well-documented roles in cancer development and progression. Plakoglobin is a cell adhesion and signaling protein and a paralog of β-catenin. Unlike β-catenin that has oncogenic function through its role in the Wnt pathway, plakoglobin generally acts as a tumor/metastasis suppressor. We have shown that plakoglobin interacted with wild type and a number of p53 mutants in various carcinoma cell lines. Plakoglobin and mutant p53 interacted with the promoter and regulated the expression of several p53 target genes. Furthermore, plakoglobin interactions with p53 mutants restored their tumor suppressor/metastasis activities in vitro. GOF p53 mutants induce accumulation and oncogenic activation of β-catenin. Previously, we showed that one mechanism by which plakoglobin may suppress tumorigenesis is by sequestering β-catenin's oncogenic activity. Here, we examined the effects of p53R175H expression on β-catenin accumulation and transcriptional activation and their modifications by plakoglobin coexpression. We showed that p53R175H expression in plakoglobin null cells increased total and nuclear levels of β-catenin and its transcriptional activity. Coexpression of plakoglobin in these cells promoted β-catenin's proteasomal degradation, and decreased its nuclear levels and transactivation. Wnt/β-catenin targets, c-MYC and S100A4 were upregulated in p53R175H cells and were downregulated when plakoglobin was coexpressed. Plakoglobin-p53R175H cells also showed significant reduction in their migration and invasion in vitro.
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Affiliation(s)
- Mahsa Alaee
- Department of OncologyUniversity of AlbertaEdmontonCanada
| | - Kristina Nool
- Department of OncologyUniversity of AlbertaEdmontonCanada
| | - Manijeh Pasdar
- Department of OncologyUniversity of AlbertaEdmontonCanada
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Göttle P, Manousi A, Kremer D, Reiche L, Hartung HP, Küry P. Teriflunomide promotes oligodendroglial differentiation and myelination. J Neuroinflammation 2018; 15:76. [PMID: 29534752 PMCID: PMC5851312 DOI: 10.1186/s12974-018-1110-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/28/2018] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease of the central nervous system (CNS) which in most cases initially presents with episodes of transient functional deficits (relapsing-remitting MS; RRMS) and eventually develops into a secondary progressive form (SPMS). Aside from neuroimmunological activities, MS is also characterized by neurodegenerative and regenerative processes. The latter involve the restoration of myelin sheaths-electrically insulating structures which are the primary targets of autoimmune attacks. Spontaneous endogenous remyelination takes place even in the adult CNS and is primarily mediated by activation, recruitment, and differentiation of resident oligodendroglial precursor cells (OPCs). However, the overall efficiency of remyelination is limited and further declines with disease duration and progression. From a therapeutic standpoint, it is therefore key to understand how oligodendroglial maturation can be modulated pharmacologically. Teriflunomide has been approved as a first-line treatment for RRMS in the USA and the European Union. As the active metabolite of leflunomide, an established disease-modifying anti-rheumatic drug, it mainly acts via an inhibition of de novo pyrimidine synthesis exerting a cytostatic effect on proliferating B and T cells. METHODS We investigated teriflunomide-dependent effects on primary rat oligodendroglial homeostasis, proliferation, and differentiation related to cellular processes important for myelin repair hence CNS regeneration in vitro. To this end, several cellular parameters, including specific oligodendroglial maturation markers, in vitro myelination, and p53 family member signaling, were examined by means of gene/protein expression analyses. The rate of myelination was determined using neuron-oligodendrocyte co-cultures. RESULTS Low teriflunomide concentrations resulted in cell cycle exit while higher doses led to decreased cell survival. Short-term teriflunomide pulses can efficiently promote oligodendroglial cell differentiation suggesting that young, immature cells could benefit from such stimulation. In vitro myelination can be boosted by means of an early stimulation window with teriflunomide. p73 signaling is functionally involved in promoting OPC differentiation and myelination. CONCLUSION Our findings indicate a critical window of opportunity during which regenerative oligodendroglial activities including myelination of CNS axons can be stimulated by teriflunomide.
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Affiliation(s)
- Peter Göttle
- Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
| | - Anastasia Manousi
- Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany
| | - David Kremer
- Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany
| | - Laura Reiche
- Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany
| | - Hans-Peter Hartung
- Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany
| | - Patrick Küry
- Department of Neurology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany
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Vazquez-Martin A, Anatskaya OV, Giuliani A, Erenpreisa J, Huang S, Salmina K, Inashkina I, Huna A, Nikolsky NN, Vinogradov AE. Somatic polyploidy is associated with the upregulation of c-MYC interacting genes and EMT-like signature. Oncotarget 2018; 7:75235-75260. [PMID: 27655693 PMCID: PMC5342737 DOI: 10.18632/oncotarget.12118] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 09/05/2016] [Indexed: 12/30/2022] Open
Abstract
The dependence of cancer on overexpressed c-MYC and its predisposition for polyploidy represents a double puzzle. We address this conundrum by cross-species transcription analysis of c-MYC interacting genes in polyploid vs. diploid tissues and cells, including human vs. mouse heart, mouse vs. human liver and purified 4n vs. 2n mouse decidua cells. Gene-by-gene transcriptome comparison and principal component analysis indicated that c-MYC interactants are significantly overrepresented among ploidy-associated genes. Protein interaction networks and gene module analysis revealed that the most upregulated genes relate to growth, stress response, proliferation, stemness and unicellularity, as well as to the pathways of cancer supported by MAPK and RAS coordinated pathways. A surprising feature was the up-regulation of epithelial-mesenchymal transition (EMT) modules embodied by the N-cadherin pathway and EMT regulators from SNAIL and TWIST families. Metabolic pathway analysis also revealed the EMT-linked features, such as global proteome remodeling, oxidative stress, DNA repair and Warburg-like energy metabolism. Genes associated with apoptosis, immunity, energy demand and tumour suppression were mostly down-regulated. Noteworthy, despite the association between polyploidy and ample features of cancer, polyploidy does not trigger it. Possibly it occurs because normal polyploidy does not go that far in embryonalisation and linked genome destabilisation. In general, the analysis of polyploid transcriptome explained the evolutionary relation of c-MYC and polyploidy to cancer.
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Affiliation(s)
| | - Olga V Anatskaya
- Institute of Cytology, St-Petersburg, Russian Federation, Russia
| | | | | | - Sui Huang
- Systems Biology Institute, Seattle, USA
| | | | - Inna Inashkina
- Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Anda Huna
- Latvian Biomedical Research and Study Centre, Riga, Latvia
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