Effect of insulin on cell cycle progression in MCF-7 breast cancer cells -Direct and potentiating influence

We recently demonstrated that in MCF-7 breast cancer cells, insulin promote d the phosphorylation and activation of geranylgeranyltransferase I (GGTI-I ), increased the amounts of geranylgeranylated Rho-A and potentiated the tr ansactivating activity of lysophosphatidic acid (LPA) (Chappell, J., Golovc henko, I., Wall, K., Stjernholm, R., Leitner, J., Goalstone, M., and Drazni n, B. (2000) J. BioL Chem. 275, 31792-31797). In the present study, we expl ored the mechanism of this potentiating effect of insulin on LPA. Insulin ( 10 nM) potentiated the ability of LPA to stimulate cell cycle progression a nd DNA synthesis in MCF-7 cells. The potentiating effect of insulin appears to involve increases in the expression of cyclin E and decreases in the ex pression of the cyclin-dependent kinase inhibitor p27(Kip1). All potentiati ng effects of insulin were inhibited in the presence of an inhibitor of GGT ase I, GGTI-286 (3 pm) or by an expression of a dominant negative mutant of Rho-A. In contrast to its potentiating action, a direct mitogenic effect o f insulin in MCF-7 cells involves activation of phosphatidylinositol 3-kina se and increased expression of cyclin D-1. We conclude that the ability of insulin to increase the cellular amounts of geranylgeranylated Rho-A result s in potentiation of the LPA effect on cyclin E expression and degradation of p27(Kip1) and cell cycle progression in MCF-7 breast cancer cells.