Farnesyl transferase inhibitors induce apoptosis of Ras-transformed cells denied substratum attachment.
Farnesyl transferase inhibitors (FTIs) are a novel class of antitumor drugs that block the oncogenic activity of Ras. Because FTIs lack significant cell toxicity in vitro and in vivo, a significant question is how they cause tumor regression. We now report that FTIs are in fact potent activators of apoptosis in Ras-transformed cells if attachment to substratum is prevented. When cultured at high density or on polyHEMA, a nonadherent substrate, Ras-transformed cells exhibited massive DNA degradation and cell death within 24 h of treatment with the FTI L-739,749. Death was p53-independent and was inhibited by the apoptosis suppressor BCL-XL. Furthermore, apoptosis was significantly attenuated by ectopic expression of a farnesyl-independent form of RhoB, a Rho protein previously implicated as a critical target for inhibition by FTIs. The findings suggest a link between FTIs and Rho-dependent adhesion signaling. Furthermore, our work indicates that FTIs revert cells to a state in which cell-substratum attachment is necessary for viability and suggests that apoptosis forms the basis for drug-induced tumor regression.
Lebowitz
P F
PF
The Wistar Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Sakamuro
D
D
Prendergast
G C
GC
D019883:Alkyl and Aryl Transferases; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion; D002452:Cell Count; D002461:Cell Line, Transformed; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D016158:Genes, p53 / Q000502:physiology; D011905:Genes, ras; D009842:Oligopeptides / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes / Q000502:physiology; D051381:Rats; D014166:Transferases / Q000037:antagonists & inhibitors*; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D003470:Culture Media; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C087363:L 739749; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase