Abstract

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 p70(s6k) phosphorylation in mammary tumors in vivo in transgenic mice. Furthermore, in a mouse keratinocyte cell line, FTI inhibits p70(s6k) 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 p70(s6k) stimulation by epidermal growth factor, demonstrating a requirement for Ras activity during p70(s6k) 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 p70(s6k) inhibition. Rapamycin, an inhibitor of p70(s6k) 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 p70(s6k) and PHAS-1 function by FTI are responsible for a substantial portion of the growth-inhibitory properties of FTI. Together, these data demonstrate that p70(s6k) 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.

Highlights

  • 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

  • MTOR was purified from mammalian cell extracts as a protein that binds to FKBP12 in a rapamycin-dependent manner [26]

  • We investigate the effect of FTI on p70s6k and PHAS-1 and find that FTI mimics the ability of rapamycin to inhibit p70s6k phosphorylation and activation, PHAS-1 phosphorylation, and DNA synthesis

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Summary

Introduction

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. The fact that rapamycin induces a G1 cell cycle arrest in many cell lines and regulates p70s6k and PHAS-1 function underscores the potential role of these proteins in mitogenic signaling.

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