IGF-1R/MDM2 relationship confers enhanced sensitivity to RITA in Ewing sarcoma cells

Giusy Di Conza, Marianna Buttarelli, Olimpia Monti, Marsha Pellegrino, Francesca Mancini, Alfredo Pontecorvi, Katia Scotlandi, Fabiola Moretti

Research output: Contribution to journalArticlepeer-review

Abstract

Ewing sarcoma is one of the most frequent bone cancers in adolescence. Although multidisciplinary therapy has improved the survival rate for localized tumors, a critical step is the development of new drugs to improve the long-term outcome of recurrent and metastatic disease and to reduce side effects of conventional therapy. Here, we show that the small molecule reactivation of p53 and induction of tumor cell apoptosis (RITA, NSC652287) is highly effective in reducing growth and tumorigenic potential of Ewing sarcoma cell lines. These effects occur both in the presence of wt-p53 as well as of mutant or truncated forms of p53, or in its absence, suggesting the presence of additional targets in this tumor histotype. Further experiments provided evidence that RITA modulates an important oncogenic mark of these cell lines, insulin-like growth factor receptor 1 (IGF-1R). Particularly, RITA causes downregulation of IGF-1R protein levels. MDM2 degradative activity is involved in this phenomenon. Indeed, inhibition of MDM2 function by genetic or pharmacologic approaches reduces RITA sensitivity of Ewing sarcoma cell lines. Overall, these data suggest that in the cell context of Ewing sarcoma, RITA may adopt additional mechanism of action besides targeting p53, expanding its field of application. Noteworthy, these results envisage the promising utilization of RITA or its derivative as a potential treatment for Ewing sarcomas.

Original languageEnglish
Pages (from-to)1247-1256
Number of pages10
JournalMolecular Cancer Therapeutics
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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