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- Title
Identification and Characterization of Mortaparib Plus —A Novel Triazole Derivative That Targets Mortalin-p53 Interaction and Inhibits Cancer-Cell Proliferation by Wild-Type p53-Dependent and -Independent Mechanisms.
- Authors
Sari, Anissa Nofita; Elwakeel, Ahmed; Dhanjal, Jaspreet Kaur; Kumar, Vipul; Sundar, Durai; Kaul, Sunil C.; Wadhwa, Renu
- Abstract
Simple Summary: Functional inactivation of tumour suppressor protein p53 is frequently found in a large variety of cancers. One of the mechanisms by which p53 is inactivated is through its interaction with mortalin protein that inhibits its translocation, and hence the function, in the nucleus. Abrogation of mortalin-p53 interaction has been suggested as a target for cancer therapy. We report here a novel multimodal small molecule, called MortaparibPlus, that causes growth arrest or apoptosis of cancer cells by abrogating mortalin-p53 interaction yielding reactivation of p53 function. It also causes upregulation of tumour suppressor protein p73, and inactivation of PARP1 and CARF proteins accounting for its multimodal anticancer activity. p53 has an essential role in suppressing the carcinogenesis process by inducing cell cycle arrest/apoptosis/senescence. Mortalin/GRP75 is a member of the Hsp70 protein family that binds to p53 causing its sequestration in the cell cytoplasm. Hence, p53 cannot translocate to the nucleus to execute its canonical tumour suppression function as a transcription factor. Abrogation of mortalin-p53 interaction and subsequent reactivation of p53's tumour suppression function has been anticipated as a possible approach in developing a novel cancer therapeutic drug candidate. A chemical library was screened in a high-content screening system to identify potential mortalin-p53 interaction disruptors. By four rounds of visual assays for mortalin and p53, we identified a novel synthetic small-molecule triazole derivative (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole, henceforth named MortaparibPlus). Its activities were validated using multiple bioinformatics and experimental approaches in colorectal cancer cells possessing either wild-type (HCT116) or mutant (DLD-1) p53. Bioinformatics and computational analyses predicted the ability of MortaparibPlus to competitively prevent the interaction of mortalin with p53 as it interacted with the p53 binding site of mortalin. Immunoprecipitation analyses demonstrated the abrogation of mortalin-p53 complex formation in MortaparibPlus-treated cells that showed growth arrest and apoptosis mediated by activation of p21WAF1, or BAX and PUMA signalling, respectively. Furthermore, we demonstrate that MortaparibPlus-induced cytotoxicity to cancer cells is mediated by multiple mechanisms that included the inhibition of PARP1, up-regulation of p73, and also the down-regulation of mortalin and CARF proteins that play critical roles in carcinogenesis. MortaparibPlus is a novel multimodal candidate anticancer drug that warrants further experimental and clinical attention.
- Subjects
APOPTOSIS; CELL proliferation; TUMOR suppressor genes
- Publication
Cancers, 2021, Vol 13, Issue 4, p835
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13040835