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Rapamycin selectively reduces the association of transcripts containing complex 5′ UTRs with ribosomes in C4‐2B prostate cancer cells
Author(s) -
Opdenaker Lynn M.,
FarachCarson Mary C.
Publication year - 2009
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22145
Subject(s) - pi3k/akt/mtor pathway , polysome , translation (biology) , prostate cancer , p70 s6 kinase 1 , protein kinase b , cancer research , ly294002 , eif4e , ribosome , microbiology and biotechnology , chemistry , protein biosynthesis , biology , cancer , signal transduction , medicine , messenger rna , biochemistry , rna , gene
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 HIF1α. 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. J. Cell. Biochem. 107: 473–481, 2009. © 2009 Wiley‐Liss, Inc.