Activation of the PI3'K-AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors.
Farnesyltransferase inhibitors (FTIs) usually cause growth inhibition, but in certain preclinical settings they have been shown to induce apoptosis, a clinically desirable response. In this study, we show that the proapoptotic effects of FTIs in Ras-transformed cells are masked by activation of phosphatidylinositol 3'-kinase (PI3'K) or AKT, which are controlled by cytokines and integrins. The results implied that FTIs disrupt a signal that is crucial for survival of malignant cells, but not normal cells, if the PI3'K-AKT pathway is inactivated. Our findings have implications for clinical applications of FTIs where apoptotic responses would be preferred.
Du
W
W
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Liu
A
A
Prendergast
G C
GC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats
D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494920:Akt1 protein, rat