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

Oncogene volume 22, pages 9282–9287 (2003)Cite this article

Abstract

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 G1 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-β type 2 receptor (TGFβ 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.

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Acknowledgements

This work was supported by US Public Health Service Grant PO1-CA74175 from the National Cancer Institute, NIH. Technical help was provided by the Flow Cytometry/Cell Sorting Shared Resource of the Lombardi Cancer Center, funded through US Public Health Service Grant P30-CA51008.

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  1. Silvia Mateo-Lozano and Oscar M Tirado: Both contributed equally to this work

Authors and Affiliations

  1. Department of Radiation Medicine, Laboratory of Experimental Carcinogenesis, Georgetown University Medical Center, Washington, DC, USA

    Silvia Mateo-Lozano, Oscar M Tirado & Vicente Notario

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  1. Silvia Mateo-Lozano
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  2. Oscar M Tirado
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Correspondence to Vicente Notario.

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Mateo-Lozano, S., Tirado, O. & Notario, V. Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation. Oncogene 22, 9282–9287 (2003). https://doi.org/10.1038/sj.onc.1207081

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