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

Domenico Di Marzo, Iris Maria Forte, Paola Indovina, Elena Di Gennaro, Valeria Rizzo, Francesca Giorgi, Eliseo Mattioli, Carmelina Antonella Iannuzzi, Alfredo Budillon, Antonio Giordano, Francesca Pentimalli

Research output: Contribution to journalArticle

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 p14ARF. 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 tumor growth in a MSTO-211H-derived xenograft model of mesothelioma and synergized with cisplatin, which is the mainstay of treatment for this tumor. Our data indicate that reactivation of p53 and concomitant p21 downregulation effectively induce cell death in mesothelioma, a tumor characterized by a high intrinsic resistance to apoptosis. Altogether, our findings provide the preclinical framework supporting the use of p53-reactivating agents alone, or in combination regimens, to improve the outcome of patients with mesothelioma.

Original languageEnglish
Pages (from-to)652-665
Number of pages14
JournalCell Cycle
Volume13
Issue number4
DOIs
Publication statusPublished - Feb 15 2014

Keywords

  • Apoptosis
  • Mesothelioma
  • Nutlin-3
  • p21
  • RITA
  • TP53 mutations

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology
  • Medicine(all)

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  • Cite this

    Di Marzo, D., Forte, I. M., Indovina, P., Di Gennaro, E., Rizzo, V., Giorgi, F., Mattioli, E., Iannuzzi, C. A., Budillon, A., Giordano, A., & Pentimalli, F. (2014). Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma. Cell Cycle, 13(4), 652-665. https://doi.org/10.4161/cc.27546