The Phosphoinositide 3-OH Kinase/AKT2 Pathway as a Critical Target for Farnesyltransferase Inhibitor-Induced Apoptosis

Abstract

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs that exhibit a remarkable ability to inhibit malignant transformation without toxicity to normal cells. However, the mechanism by which FTIs inhibit tumor growth is not well understood. Here, we demonstrate that FTI-277 inhibits phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2-mediated growth 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 notAKT2-transformed NIH 3T3 cells. A constitutively active form of AKT2 rescues human cancer cells from FTI-277-induced apoptosis. FTI-277 inhibits insulin-like growth factor 1-induced PI 3-kinase and AKT2 activation and subsequent phosphorylation of the proapoptotic protein BAD. Integrin-dependent activation 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.

ACKNOWLEDGMENTS

We are grateful to Michael E. Greenberg for GST-Bad plasmids; Alan Hall for RhoB constructs; Thomas C. Hamilton for ovarian cancer cell lines; Andres J. P. Klein-Szanto for pancreatic cancer cell lines; Sue A. Shelley and Richard I. Feldman for constructive comments; June E. Paciga, Ai-xie Liu and Jie-liu Tang for technical support; and Wen-ching Lee for critical reading and comments on the manuscript. We are also grateful to DNA Sequence Facility at H. Lee Moffitt Cancer Center for sequencing AKT2 expression constructs.

This work was supported by grants CA-77935 (J.Q.C.) and CA-67771 (S.M.S. and A.D.H.) from the National Cancer Institute and grant 6115-000-20 (S.V.N.) from University of South Florida.