|
|
Ras Inhibition in Glioblastoma Down-regulates
Hypoxia-Inducible Factor-1{alpha}, Causing Glycolysis Shutdown and Cell
Death
Blum R, Jacob-Hirsch J, Amariglio N, Rechavi G, Kloog Y
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences and
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel and
Department of Pediatric Hematology-Oncology, Safra Children's Hospital,
Sheba Medical Center, Tel Hashomer, Israel.
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.
PMID: 15705901 [PubMed - as supplied by publisher]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15705901
|
