title: IGF-1R/MDM2 relationship confers enhanced sensitivity to RITA in Ewing sarcoma cells.
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.
authors.affiliation: Cell Biology and Neurobiology Institute-CNR/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Giusy
authors.initials: G
authors.lastname: Di Conza
authors.forename: Marianna
authors.initials: M
authors.lastname: Buttarelli
authors.forename: Olimpia
authors.initials: O
authors.lastname: Monti
authors.forename: Marsha
authors.initials: M
authors.lastname: Pellegrino
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
authors.forename: Fabiola
authors.initials: F
authors.lastname: Moretti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; C118989:NSC 652287; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017526:Receptor, IGF Type 1