Inhibition of DNA Synthesis by a Farnesyltransferase Inhibitor Involves Inhibition of the p70 super(s6k) Pathway

• Published in: The Journal of biological chemistry Vol. 274; no. 8; pp. 4743 - 4748
• Main Authors: Law, B K, Noergaard, P, Gnudi, L, Kahn, B B, Poulson, H S, Moses, H L
• Format: Journal Article
• Language: English
• Published: 19-02-1999
• ISSN: 0021-9258

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 super(s6k) phosphorylation in mammary tumors in vivo in transgenic mice. Furthermore, in a mouse keratinocyte cell line, FTI inhibits p70 super(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 super(s6k) stimulation by epidermal growth factor, demonstrating a requirement for Ras activity during p70 super(s6k) activation. FTI does not inhibit protein kinase B phosphorylation on Ser super(473), 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 super(s6k) inhibition. Rapamycin, an inhibitor of p70 super(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 super(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 super(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.