Mutant p53L194F Harboring Luminal-A Breast Cancer Cells Are Refractory to Apoptosis and Cell Cycle Arrest in Response to MortaparibPlus, a Multimodal Small Molecule Inhibitor

Ahmed Abdelmageed Saad Ahmed Elwakeel, Anissa Nofita Sari, Jaspreet Kaur Dhanjal, Hazna Noor Meidinna, Durai Sundar, Sunil C. Kaul, Renu Wadhwa

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    Abstract

    We previously performed a drug screening to identify a potential inhibitor of mortalin–p53 interaction. In four rounds of screenings based on the shift in mortalin immunostaining pattern from perinuclear to pan-cytoplasmic and nuclear enrichment of p53, we had identified MortaparibPlus (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) as a novel synthetic small molecule. In order to validate its activity and mechanism of action, we recruited Luminal-A breast cancer cells, MCF-7 (p53wild type) and T47D (p53L194F) and performed extensive biochemical and immunocytochemical analyses. Molecular analyses revealed that MortaparibPlus is capable of abrogating mortalin–p53 interaction in both MCF-7 and T47D cells. Intriguingly, upregulation of transcriptional activation function of p53 (as marked by upregulation of the p53 effector gene—p21WAF1—responsible for cell cycle arrest and apoptosis) was recorded only in MortaparibPlus-treated MCF-7 cells. On the other hand, MortaparibPlus-treated T47D cells exhibited hyperactivation of PARP1 (accumulation of PAR polymer and decrease in ATP levels) as a possible non-p53 tumor suppression program. However, these cells did not show full signs of either apoptosis or PAR-Thanatos. Molecular analyses attributed such a response to the inability of MortaparibPlus to disrupt the AIF–mortalin complexes; hence, AIF did not translocate to the nucleus to induce chromatinolysis and DNA degradation. These data suggested that the cancer cells possessing enriched levels of such complexes may not respond to MortaparibPlus. Taken together, we report the multimodal anticancer potential of MortaparibPlus that warrants further attention in laboratory and clinical studies.
    Original languageEnglish
    Article number3043
    Number of pages24
    JournalCancers
    Volume13
    Issue number12
    DOIs
    Publication statusPublished - 18 Jun 2021

    Bibliographical note

    Copyright: © 2021 by the authors.
    Licensee MDPI, Basel, Switzerland.
    This article is an open access article
    distributed under the terms and
    conditions of the Creative Commons
    Attribution (CC BY) license (https://
    creativecommons.org/licenses/by/
    4.0/).

    Keywords

    • tumor suppression
    • ATP
    • DNA Damage
    • PARP1 hyperactivation
    • mortalin–p53 interaction
    • luminal-A breast cancer cells
    • MortaparibPlus

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