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J. Biol. Chem., Vol. 276, Issue 41, 38023-38028, October 12, 2001

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Effect of Insulin on Cell Cycle Progression in MCF-7 Breast Cancer Cells
DIRECT AND POTENTIATING INFLUENCE^*

James Chappell, J. Wayne Leitner, Scott Solomon, Inga Golovchenko, Marc L. Goalstone, and Boris Draznin^§

From the Research Service of the Department of Veterans Affairs, Denver, Colorado 80220

We recently demonstrated that in MCF-7 breast cancer cells, insulin promoted the phosphorylation and activation of geranylgeranyltransferase I (GGTI-I), increased the amounts of geranylgeranylated Rho-A and potentiated the transactivating activity of lysophosphatidic acid (LPA) (Chappell, J., Golovchenko, I., Wall, K., Stjernholm, R., Leitner, J., Goalstone, M., and Draznin, B. (2000) J. Biol. Chem. 275, 31792-31797). In the present study, we explored the mechanism of this potentiating effect of insulin on LPA. Insulin (10 nM) potentiated the ability of LPA to stimulate cell cycle progression and 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 expression of the cyclin-dependent kinase inhibitor p27^Kip1. All potentiating effects of insulin were inhibited in the presence of an inhibitor of GGTase I, GGTI-286 (3 µM) or by an expression of a dominant negative mutant of Rho-A. In contrast to its potentiating action, a direct mitogenic effect of insulin in MCF-7 cells involves activation of phosphatidylinositol 3-kinase and increased expression of cyclin D₁. We conclude that the ability of insulin to increase the cellular amounts of geranylgeranylated Rho-A results 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.

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