Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death.
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 1alpha (HIF-1alpha) disappeared, expression of key glycolysis pathway enzymes and of other HIF-1alpha-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-1alpha and might therefore block invasiveness, survival, and angiogenesis in GBM.
Blum
Roy
R
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences and Sackler School of Medicine, Tel-Aviv University, 66978 Tel-Aviv, Israel.
Jacob-Hirsch
Jasmine
J
Amariglio
Ninette
N
Rechavi
Gideon
G
Kloog
Yoel
Y
D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012459:Salicylates; D014157:Transcription Factors; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins