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J Biol Chem, Vol. 274, Issue 8, 4743-4748, February 19, 1999

Inhibition of DNA Synthesis by a Farnesyltransferase Inhibitor Involves Inhibition of the p70s6k Pathway

Brian K. LawDagger §, Peter Nørgaardparallel , Luigi Gnudi**, Barbara B. Kahn**, Hans S. Poulsonparallel , and Harold L. MosesDagger §

From the Dagger  Vanderbilt Cancer Center and § Department of Cell Biology, Vanderbilt University, Nashville, Tennessee 37232, the parallel  Section for Radiation Biology, The Finsen Center Rigshospitalet, Copenhagen DK-2100, Denmark, and the ** Diabetes Unit, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Previously, the protein farnesyltransferase inhibitor (FTI), L-744,832, has been shown to inhibit the proliferation of a number of tumor cell lines in vitro in a manner that correlated with the inhibition of the mitogen-activated protein kinase cascade. Here we show that FTI inhibits p70s6k phosphorylation in mammary tumors in vivo in transgenic mice. Furthermore, in a mouse keratinocyte cell line, FTI inhibits p70s6k phosphorylation and activity and inhibits PHAS-1 phosphorylation in vitro in both rapidly growing cells and in growth factor-stimulated quiescent cells. Dominant-negative Ras expression inhibits p70s6k stimulation by epidermal growth factor, demonstrating a requirement for Ras activity during p70s6k activation. FTI does not inhibit protein kinase B phosphorylation on Ser473, indicating that FTI does not act by inhibiting phosphatidylinositol 3-kinase. FTI also inhibits DNA synthesis in keratinocytes, and inhibition of DNA synthesis correlates closely with p70s6k inhibition. Rapamycin, an inhibitor of p70s6k and PHAS-1 phosphorylation, causes a 30-45% reduction in DNA synthesis in keratinocytes, while FTI induces an 80-90% reduction in DNA synthesis. These observations suggest that alteration of p70s6k and PHAS-1 function by FTI are responsible for a substantial portion of the growth-inhibitory properties of FTI. Together, these data demonstrate that p70s6k and PHAS-1 are novel downstream targets of FTI and suggest that the anti-tumor properties of FTI are probably due to the inhibition of multiple mitogenic pathways.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.


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