Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma

Cell Cycle
D Di MarzoF Pentimalli

Abstract

Malignant mesothelioma, a very aggressive tumor associated to asbestos exposure, is expected to increase in incidence, and unfortunately, no curative modality exists. Reactivation of p53 is a new attractive antitumoral strategy. p53 is rarely mutated in mesothelioma, but it is inactivated in most tumors by the lack of p14(ARF). Here, we evaluated the feasibility of this approach in pleural mesothelioma by testing RITA and nutlin-3, two molecules able to restore p53 function through a different mechanism, on a panel of mesothelioma cell lines representing the epithelioid (NCI-H28, NCI-H2452, IST-MES 2), biphasic (MSTO-211H), and sarcomatoid (NCI-H2052) histotypes compared with the normal mesothelial HMC-hTERT. RITA triggered robust caspase-dependent apoptosis specifically in epithelioid and biphasic mesothelioma cell lines, both through wild-type and mutant p53, concomitant to p21 downregulation. Conversely, nutlin-3 induced a p21-dependent growth arrest, rather than apoptosis, and was slightly toxic on HMC-hTERT.   Interestingly, we identified a previously undetected point mutation of p53 (p.Arg249Ser) in IST-MES 2, and showed that RITA is also able to reactivate this p53 mutant protein and its apoptotic function. RITA reduced ...Continue Reading

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Citations

Dec 17, 2014·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Marco Lo IaconoGiorgio V Scagliotti
Jun 16, 2018·Journal of Cellular Physiology·Eleonora SementinoJoseph R Testa
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Jan 13, 2015·World Journal of Gastroenterology : WJG·Xiao-Lan LiWee-Joo Chng
Oct 15, 2018·Journal of Translational Medicine·Kun TianMarija Krstic-Demonacos
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Nov 27, 2020·Therapeutic Advances in Medical Oncology·Haitang YangRen-Wang Peng
Sep 15, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Emily S ReardonDavid S Schrump

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