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[Cancer Research 65, 999-1006, February 1, 2005]
© 2005 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Ras Inhibition in Glioblastoma Down-regulates Hypoxia-Inducible Factor-1{alpha}, Causing Glycolysis Shutdown and Cell Death

Roy Blum1, Jasmine Jacob-Hirsch3, Ninette Amariglio3, Gideon Rechavi2,3 and Yoel Kloog1

1 Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences and 2 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel and 3 Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel

Requests for reprints: Yoel Kloog, Department of Neurobiochemistry, 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: yoelk{at}tauex.tau.ac.il.

Active Ras and phosphatidylinositol-3-kinase–dependent pathways contribute to the malignant phenotype of glioblastoma multiformes (GBM). Here we show that the Ras inhibitor trans-farnesylthiosalicylic acid (FTS) exhibits profound antioncogenic effects in U87 GBM cells. FTS inhibited active Ras and attenuated Ras signaling to extracellular signal-regulated kinase, phosphatidylinositol-3-kinase, and Akt. Concomitantly, hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) disappeared, expression of key glycolysis pathway enzymes and of other HIF-1{alpha}–regulated genes (including vascular endothelial growth factor and the Glut-1 glucose transporter) was down-regulated, and glycolysis was halted. This led to a dramatic reduction in ATP, resulting in a severe energy crisis. In addition, the expression of E2F-regulated genes was down-regulated in the FTS-treated cells. Consequently, U87 cell growth was arrested and the cells died. These results show that FTS is a potent down-regulator of HIF-1{alpha} and might therefore block invasiveness, survival, and angiogenesis in GBM.

Key Words: Ras • hypoxia-inducible factor-1{alpha} • glioblastoma • Ras inhibitors • FTS




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Copyright © 2005 by the American Association for Cancer Research.