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Research Articles: Therapeutics

Suppression of survivin expression in glioblastoma cells by the Ras inhibitor farnesylthiosalicylic acid promotes caspase-dependent apoptosis

¹ Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences and ² Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Requests for reprints: Yoel Kloog, Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel. Phone: 972-3-640-9699; Fax: 972-3-640-7643. E-mail: kloog{at}post.tau.ac.il

The Ras inhibitor farnesylthiosalicylic acid (FTS) has been shown to induce apoptosis in glioblastoma multiforme, but its mechanism of action was unknown. We show that FTS or dominant-negative Ras, by deregulating extracellular signal-regulated kinase and Akt signaling, decreases survivin gene transcripts in U87 glioblastoma multiforme, leading to disappearance of survivin protein and cell death. FTS affected both Ras-controlled regulators of survivin transcription and Ras-regulated survival signals. Thus, Ras inhibition by FTS resulted in release of the survivin "brake" on apoptosis and in activation of the mitochondrial apoptotic pathway: dephosphorylation of Bad, activation of Bax, release of cytochrome c, and caspase activation. FTS-induced apoptosis of U87 cells was strongly attenuated by forced expression of survivin or by caspase inhibitors. These results show that resistance to apoptosis in glioblastoma multiforme can be abolished by a single Ras inhibitor, which targets both survivin, a critical inhibitor of apoptosis, and the intrinsic mitochondrial apoptotic machinery. [Mol Cancer Ther 2006;5(9):2337–47]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y. Kloog is the incumbent of the Jack H. Skirball Chair for Applied Neurobiology. G. Rechavi is the incumbent of the Djerassi Chair in Oncology.

³ http://www.eng.sheba.co.il/genomics.

Received 4/10/06; revised 6/10/06; accepted 7/26/06.

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