Abstract

mTOR pathway inhibitors, specifically rapamycin and its derivatives, are promising therapeutics that targets downstream pathways including protein translation. We examined the effects of a series of inhibitors targeting various pathways on ribosomal polysome distribution, overall translation rates, and translation of specific mRNAs in the bone derived prostate cancer cell line, C4-2B. Treatment with either rapamycin, PD98059 or LY294002 failed to change the distribution of polysomes in sucrose gradients. Although no change in the accumulation of heavy polysomes was observed, there was an overall decrease in the rate of translation caused by treatment with rapamycin or LY294002. Inhibiting the MAPK pathway with PD98059 decreased overall translation by 20%, but had no effect on mRNAs containing a 5' terminal oligopyrimidine tract (TOP) sequences or those with complex 5' UTRs. In contrast, treatment with rapamycin for 24 h reduced overall translation by approximately 45% and affected the translation of mRNAs with complex 5' UTRs, specifically VEGF and HIF1alpha. After 24 h, LY294002 treatment alone decreased overall translation by 60%, more than was observed with rapamycin. Although LY294002 and similar inhibitors are effective at blocking prostate cancer cell growth, they act upstream of AKT and PTEN and cancer cells can find a way to bypass this inhibition. Thus, we propose that inhibiting downstream targets such as mTOR or targets of mTOR will provide rational approaches to developing new combination therapies focused on reducing growth of prostate cancer after arrival in the bone environment.

(c) 2009 Wiley-Liss, Inc.