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.
Description
Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death. - PubMed - NCBI
%0 Journal Article
%1 Blum:2005:Cancer-Res:15705901
%A Blum, R
%A Jacob-Hirsch, J
%A Amariglio, N
%A Rechavi, G
%A Kloog, Y
%D 2005
%J Cancer Res
%K SHOULDREAD cancer-research fulltext glioblastoma ras
%N 3
%P 999-1006
%T Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death
%U https://www.ncbi.nlm.nih.gov/pubmed/15705901
%V 65
%X 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.
@article{Blum:2005:Cancer-Res:15705901,
abstract = {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.},
added-at = {2018-07-08T09:50:15.000+0200},
author = {Blum, R and Jacob-Hirsch, J and Amariglio, N and Rechavi, G and Kloog, Y},
biburl = {https://www.bibsonomy.org/bibtex/2bd82078acb4cad7d1b5cde50afb3c44e/marcsaric},
description = {Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death. - PubMed - NCBI},
interhash = {17db24b15e11cf8f08f51867150cc963},
intrahash = {bd82078acb4cad7d1b5cde50afb3c44e},
journal = {Cancer Res},
keywords = {SHOULDREAD cancer-research fulltext glioblastoma ras},
month = feb,
number = 3,
pages = {999-1006},
pmid = {15705901},
timestamp = {2018-07-08T09:50:38.000+0200},
title = {Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death},
url = {https://www.ncbi.nlm.nih.gov/pubmed/15705901},
volume = 65,
year = 2005
}