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Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells
Author(s) -
YacqubUsman Kiren,
Pickard Mark R.,
Williams Gwyn T.
Publication year - 2015
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22952
Subject(s) - gas5 , pi3k/akt/mtor pathway , lncap , prostate cancer , cancer research , cell growth , mtorc1 , cancer cell , biology , cancer , medicine , downregulation and upregulation , signal transduction , long non coding rna , microbiology and biotechnology , biochemistry , gene
BACKGROUND New therapies are required for castrate‐resistant prostate cancer (CRPC), and growth‐arrest specific 5 (GAS5) lncRNA, which riborepresses androgen receptor action, may offer novel opportunities in this regard. This lncRNA promotes the apoptosis of prostate cancer cells and its levels decline as prostate cancer cells acquire castrate‐resistance, so that enhancing GAS5 expression may improve the effectiveness of chemotherapies. Since GAS5 is a member of the 5' terminal oligopyrimidine gene family, we have examined mTOR inhibition as a strategy to increase GAS5 expression. Furthermore, we have determined if GAS5 itself mediates the action of mTOR inhibitors, as demonstrated for other chemotherapeutic agents in prostate cancer cells. METHODS The effects of mTOR inhibitors on GAS5 lncRNA levels and cell growth were determined in a range of prostate cancer cell lines. Transfection of cells with GAS5 siRNAs and plasmid constructs was performed to determine the involvement of GAS5 lncRNA in mTOR inhibitor action. RESULTS First generation mTORC1, combined mTORC1/mTORC2 and dual PI3K/mTOR inhibitors all increased cellular GAS5 levels and inhibited culture growth in androgen‐dependent (LNCaP) and androgen‐sensitive (22Rv1) cell lines, but not in androgen‐independent (PC‐3 and DU 145) cell lines. The latter exhibited low endogenous GAS5 expression, and GAS5 silencing in LNCaP and 22Rv1 cells decreased the sensitivity to mTOR inhibitors, whereas transfection of GAS5 lncRNA sensitized PC‐3 and DU 145 cells to these agents. CONCLUSION mTOR inhibition enhances GAS5 transcript levels in certain prostate cancer cell lines. This selectivity is likely to be related to endogenous GAS5 expression levels, since GAS5 lncRNA is itself required for mTOR inhibitor action in prostate cancer cells. Prostate 75:693–705, 2015 . © 2015 Wiley Periodicals, Inc.