p53 reactivating small molecule PRIMA‑1<sup>MET</sup>/APR‑246 regulates genomic instability in MDA‑MB‑231 cells

Amirtharaj,Francis; Venkatesh,Goutham Hassan; Wojtas,Bartosz; Nawafleh,Hussam Hussein; Mahmood,Ayda Shah; Nizami,Zohra Nausheen; Khan,Munazza Samar; Thiery,Jerome; Chouaib,Salem

doi:10.3892/or.2022.8296

April-2022 Volume 47 Issue 4

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April-2022 Volume 47 Issue 4

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Article

p53 reactivating small molecule PRIMA‑1^MET/APR‑246 regulates genomic instability in MDA‑MB‑231 cells

Authors:
- Francis Amirtharaj
- Goutham Hassan Venkatesh
- Bartosz Wojtas
- Hussam Hussein Nawafleh
- Ayda Shah Mahmood
- Zohra Nausheen Nizami
- Munazza Samar Khan
- Jerome Thiery
- Salem Chouaib
View Affiliations / Copyright

Affiliations: Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates, Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, PAS, 02‑093 Warsaw, Poland, INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris‑Saclay, F‑94805 Villejuif, France
Article Number: 85
|
Published online on: March 1, 2022

https://doi.org/10.3892/or.2022.8296
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Abstract

Pharmacological reactivation of tumor‑suppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a non‑functional mutant p53 (mutp53). p53 plays a critical role in preserving genomic integrity and DNA fidelity through numerous biological processes, including cell cycle arrest, DNA repair, senescence and apoptosis. By contrast, non‑functional mutp53 compromises the aforementioned genome stabilizing mechanisms through gain of function, thereby increasing genomic instability in human cancers. Restoring the functional activity of p53 using both genetic and pharmacological approaches has gained prominence in targeting p53‑mutated tumors. Thus, the present study aimed to investigate the reactivation of p53 in DNA repair mechanisms and the maintenance of genomic stability using PRIMA‑1^MET/APR‑246 small molecules, in both MDA‑MB‑231 and MCF‑7 breast cancer cell lines, which carry mutp53 and wild‑type p53, respectively. Results of the present study revealed that reactivation of p53 through APR‑246 led to an increase in the functional activity of DNA repair. Prolonged treatment of MDA‑MB‑231 cells with APR‑246 in the presence of cisplatin led to a reduction in mutational accumulation, compared with cells treated with cisplatin alone. These findings demonstrated that APR‑246 may act as a promising small molecule to control the genomic instability in p53‑mutated tumors.

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