Farnesyltransferase inhibitor induces rapid growth arrest and blocks p70s6k activation by multiple stimuli

We have previously shown that the peptidomimetic farnesyltransferase inhibi tor L-744,832 (FTI) inhibits p70s6k activation and cell growth in a mouse k eratinocyte cell line but only at concentrations of FTI significantly highe r than those required for the inhibition of Ras farnesylation, Here we show that the rapid kinetics of FTI inhibition of DNA synthesis (within 1.5 h) in both normal and v-K-Ras transformed keratinocytes matches the rapid kine tics of p70s6k inhibition observed previously. It is further shown that FTI inhibits p70s6k activation in response to serum, phorbol myristate acetate , and increased amino acid levels. The phosphatase inhibitor calyculin A pa rtially reverses the FTI-induced dephosphorylation of p70s6k, suggesting th at FTI may act upstream of a protein phosphatase. A rapamycin-resistant mut ant of p70s6k is shown to be resistant to FTI-induced dephosphorylation of the major rapamycin-sensitive phosphorylation site of p70s6k, Thr(389). Tog ether, these data demonstrate that FTI rapidly inhibits DNA synthesis irres pective of the presence of v-K-Ras and that FTI inhibits p70s6k activation in response to multiple stimuli. Because the FTI L-744,832 mimics many of t he effects of rapamycin, this FTI may prove effective against tumors that e xhibit inappropriate activation of the mTOR/p70s6k pathway.