Bk. Law et al., Inhibition of DNA synthesis by a farnesyltransferase inhibitor involves inhibition of the p70(s6k) pathway, J BIOL CHEM, 274(8), 1999, pp. 4743-4748
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-activ
ated protein kinase cascade. Here we show that FTI inhibits p70(s6k) phosph
orylation in mammary tumors in vivo in transgenic mice. Furthermore, in a m
ouse keratinocyte cell line, FTI inhibits p70(s6k) phosphorylation and acti
vity and inhibits PHAS-1 phosphorylation in vitro in both rapidly growing c
ells and in growth factor-stimulated quiescent cells, Dominant-negative Ras
expression inhibits p70(s6k) stimulation by epidermal growth factor, demon
strating a requirement for Pas activity during p70(s6k) activation. FTI doe
s not inhibit protein kinase B phosphorylation on Ser(473), indicating that
FTI does not act by inhibiting phosphatidylinositol 3-kinase, FTI also inh
ibits DNA synthesis in keratinocytes, and inhibition of DNA synthesis corre
lates 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. Thes
e observations suggest that alteration of p70(s6k) and PHAS-1 function by F
TI are responsible for a substantial portion of the growth-inhibitory prope
rties of FTI. Together, these data demonstrate that p70S6k and PHAS-1 are n
ovel downstream targets of FTI and suggest that the antitumor properties of
FTI are probably due to the inhibition of multiple mitogenic pathways.