PT  - JOURNAL ARTICLE
AU  - Chun-Ki Kim
AU  - Yoon-Kyoung Choi
AU  - Hansoo Lee
AU  - Kwon-Soo Ha
AU  - Moo-Ho Won
AU  - Young-Geun Kwon
AU  - Young-Myeong Kim
TI  - The Farnesyltransferase Inhibitor LB42708 Suppresses VEGF-induced Angiogenesis by Inhibiting Ras-dependent MAPK and PI3K/Akt Signal Pathways
AID  - 10.1124/mol.110.063586
DP  - 2010 Apr 20
TA  - Molecular Pharmacology
PG  - mol.110.063586
4099  - http://molpharm.aspetjournals.org/content/early/2010/04/20/mol.110.063586.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/04/20/mol.110.063586.full
AB  - Farnesyltransferase (FTase) inhibitors induce growth arrest and apoptosis in various human cancer cells by inhibiting the post-translational activation of Ras. FTase inhibitors also function to suppress the release of vascular endothelial growth factor (VEGF) from tumor cells by inhibiting Ras activation; however, the effects of FTase inhibitors on VEGF-induced angiogenesis in endothelial cells have not been studied. We have investigated the anti-angiogenic effect and molecular mechanism of LB42708, a selective non-peptidic FTase inhibitor, using in vitro and in vivo assay systems. LB42708 inhibited VEGF-induced Ras activation and subsequently suppressed angiogenesis in vitro and in vivo by blocking the MEK/ERK/p38 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt/eNOS pathways in endothelial cells, without altering FAK/Src activation. In addition, this inhibitor suppressed VEGF-induced endothelial cell cycle progression at the G1 phase by suppressing cyclin D1 expression and Rb phosphorylation as well as upregulating the cyclin-dependent kinase inhibitors p21 and p27. Knockdown of Ras by siRNA revealed similar inhibitory effects on VEGF-induced angiogenic signal events as compared to LB42708. Moreover, the inhibitory effects of LB42708 were significantly higher than those of SCH66336, a well-known FTase inhibitor. LB42708 suppressed tumor growth and tumor angiogenesis in both xenograft tumor models of Ras-mutated HCT116 cells and its wild-type Caco-2 cells, indicating its potential application in the treatment for both Ras-mutated and wild type tumors. These data indicate that the anti-tumor effect of LB42708 can be associated with direct inhibition of VEGF-induced tumor angiogenesis by blocking Ras-dependent MAPK and PI3K/Akt signal pathways in tumor-associated endothelial cells.The American Society for Pharmacology and Experimental Therapeutics