Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation

被引:79
作者
Mateo-Lozano, S [1 ]
Tirado, OM [1 ]
Notario, V [1 ]
机构
[1] Georgetown Univ, Med Ctr, Dept Radiat Med, Expt Carcinogenesis Lab, Washington, DC 20057 USA
关键词
mTOR; rapamycin; EWS/FLI-1; Ewing's sarcoma;
D O I
10.1038/sj.onc.1207081
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ewing's sarcoma (ES) is the prototype of a family of tumors (ESFT) of neuroectodermal origin formed by small, round cells with limited neural differentiation, which arise most frequently within bones in children or adolescents. The proliferation of ESFT cells is highly dependent on the establishment of, and signaling through several growth factor-mediated autocrine loops. The mammalian target of rapamycin (mTOR) is a central regulator of translation and cell proliferation, involved in the cellular response to various nutritional, stress and mitogenic effectors. As mTOR has recently been associated with certain human cancers, we investigated the possibility that mTOR played a role in the regulation of ES cell proliferation. Results showed that ES cell lines carrying EWS/FLI-1 alleles of different types expressed different levels of total and phosphorylated mTOR protein. We demonstrate that rapamycin, an mTOR inhibitor, efficiently blocked the proliferation of all cell lines by promoting cell cycle arrest at the G(1) phase. This was paralleled by the downregulation of the levels of the EWS/FLI-1 proteins, regardless of their fusion type, and the concomitant restoration of the expression of the TGF-beta type 2 receptor (TGFbeta RII), which is known to be repressed by several EWS-ETS fusion proteins. The expression of a rapamycin-resistant mTOR construct prevented both the proliferation blockade and the EWS/FLI-1 downregulation. These data demonstrate that mTOR signaling plays a central role in ES cell pathobiology and strongly suggest that the use of rapamycin as a cytostatic agent may be an efficient tool for the treatment of ES patients.
引用
收藏
页码:9282 / 9287
页数:6
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