Thumbnail Image
Publication

Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells.

Yacqub-Usman, Kiren
; 
Pickard, Mark R.
; 
Williams, Gwyn T.
Advisors
Editors
Other Contributors
Affiliation
Keele University
EPub Date
Publication Date
2015-02-03
Submitted Date
Collections
Chester Medical School
Show all metadata
Files
Thumbnail Image
Main article
Adobe PDF, 950.28 KB
Other Titles
Abstract
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.
Citation
Yacqub-Usman, K., Pickard, M. R., & Williams, G. T. (2015). Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate, 75(7), 693-705. DOI: 10.1002/pros.22952
Publisher
Wiley
Journal
Prostate
Research Unit
URI
http://hdl.handle.net/10034/609538
DOI
10.1002/pros.22952
PubMed ID
PubMed Central ID
Type
Article
Language
en
Description
This is the peer reviewed version of the following article: Yacqub-Usman, K., Pickard, M. R., & Williams, G. T. (2015). Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate, 75(7), 693-705. DOI: 10.1002/pros.22952, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/pros.22952/abstract;jsessionid=B9892067CCD9082275B1EFFFC59926F6.f02t02. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
Series/Report no.
ISSN
EISSN
1097-0045
ISBN
ISMN
Gov't Doc
Test Link
Sponsors
Prostate Cancer Collaborative, United Kingdom (PCUK)
Additional Links
http://onlinelibrary.wiley.com/doi/10.1002/pros.22952/abstract;jsessionid=B9892067CCD9082275B1EFFFC59926F6.f02t02