The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs that exhibit a remarkable ability to inhibit malignant transformatio n without toxicity to normal cells. However, the mechanism by which FTIs in hibit tumor growth is not well understood. Here, we demonstrate that FTI-27 7 inhibits phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2-mediated gro wth factor- and adhesion-dependent survival pathways and induces apoptosis in human cancer cells that overexpress AKT2. Furthermore, overexpression of AKT2, but not oncogenic H-Ras, sensitizes NIH 3T3 cells to FTI-277, and a high serum level prevents FTI-277-induced apoptosis in H-Ras- but not AKT2- transformed NIH 3T3 cells. A constitutively active form of AKT2 rescues hum an cancer cells from FTI-277-induced apoptosis. FTI-277 inhibits insulin-li ke growth factor 1-induced PI 3-kinase and AKT2 activation and subsequent p hosphorylation of the proapoptotic protein BAD. Integrin-dependent activati on of AKT2 is also blocked by FTI-277. Thus, a mechanism for FTI inhibition of human tumor growth is by inducing apoptosis through inhibition of PI 3- kinase/AKT2-mediated cell survival and adhesion pathway.