Caveolin-1 is a target of EWS/FLI-1 and a key determinant of tumorigenicity and resistance to chemotherapy-induced apoptosis of Ewing's sarcoma cells.

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Tumors of the Ewing's sarcoma family (ESFT), such as Ewing's sarcoma (EWS) and primitive neuroectodermal tumors (PNET), are highly aggressive malignancies predominantly affecting children and adolescents. ESFT express chimeric transcription factors encoded by hybrid genes fusing the EWS gene with several ETS genes, most commonly FLI-1. EWS/FLI-1 proteins are responsible for the malignant phenotype of ESFT, but only few of their transcriptional targets are known. Using antisense-mediated knockdown and gene array strategies, we demonstrate that caveolin-1 is a new direct target of EWS/FLI-1 that is over-expressed in ESFT cell lines and tumor specimens, and is necessary for ESFT tumorigenesis. Caveolin-1 knockdown led to upregulation of Snail and the concomitant loss of E-cadherin expression. Consistently, loss of caveolin-1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of EWS cell-derived tumors in nude mice xenografts, indicating that caveolin-1 promotes the malignant phenotype in EWS carcinogenesis. Furthermore, we also demonstrate that caveolin-1 increases the resistance of EWS to cisplatin-induced apoptosis by a mechanism involving PKCα. These data identify caveolin-1 as a key determinant of the tumorigenicity and chemotherapeutic response of ESFT, and imply that targeting caveolin-1 may allow the development of new molecular therapeutic strategies for ESFT patients.