Article ; Online: IGF-1R/MDM2 relationship confers enhanced sensitivity to RITA in Ewing sarcoma cells.
2012 Volume 11, Issue 6, Page(s) 1247–1256
Abstract: ... apoptosis (RITA, NSC652287) is highly effective in reducing growth and tumorigenic potential ... 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 ...
| 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. |
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| MeSH term(s) | Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis ; Bone Neoplasms/drug therapy ; Bone Neoplasms/metabolism ; Bone Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation ; Down-Regulation ; Furans/pharmacology ; Furans/therapeutic use ; Humans ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Receptor, IGF Type 1/antagonists & inhibitors ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; Sarcoma, Ewing/drug therapy ; Sarcoma, Ewing/metabolism ; Sarcoma, Ewing/pathology ; Tumor Suppressor Protein p53/metabolism |
| Chemical Substances | Antineoplastic Agents ; Furans ; NSC 652287 ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Receptor, IGF Type 1 (EC 2.7.10.1) |
| Language | English |
| Publishing date | 2012-03-28 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2063563-1 |
| ISSN | 1538-8514 ; 1535-7163 |
| ISSN (online) | 1538-8514 |
| ISSN | 1535-7163 |
| DOI | 10.1158/1535-7163.MCT-11-0913 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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