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

Hdl Handle:
http://hdl.handle.net/10034/609538
Title:
Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells.
Authors:
Yacqub-Usman, Kiren; Pickard, Mark R.; Williams, Gwyn T.
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.
Affiliation:
Keele University
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
Publication Date:
3-Feb-2015
URI:
http://hdl.handle.net/10034/609538
DOI:
10.1002/pros.22952
Additional Links:
http://onlinelibrary.wiley.com/doi/10.1002/pros.22952/abstract;jsessionid=B9892067CCD9082275B1EFFFC59926F6.f02t02
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
EISSN:
1097-0045
Sponsors:
Prostate Cancer Collaborative, United Kingdom (PCUK)
Appears in Collections:
Institute of Medicine

Full metadata record

DC FieldValue Language
dc.contributor.authorYacqub-Usman, Kirenen
dc.contributor.authorPickard, Mark R.en
dc.contributor.authorWilliams, Gwyn T.en
dc.date.accessioned2016-05-17T09:12:55Zen
dc.date.available2016-05-17T09:12:55Zen
dc.date.issued2015-02-03en
dc.identifier.citationYacqub-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.22952en
dc.identifier.doi10.1002/pros.22952en
dc.identifier.other25650269en
dc.identifier.urihttp://hdl.handle.net/10034/609538en
dc.descriptionThis 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-Archivingen
dc.description.abstractBACKGROUND: 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.en
dc.description.sponsorshipProstate Cancer Collaborative, United Kingdom (PCUK)en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urlhttp://onlinelibrary.wiley.com/doi/10.1002/pros.22952/abstract;jsessionid=B9892067CCD9082275B1EFFFC59926F6.f02t02en
dc.rights.urihttp://creativecommons.org/publicdomain/mark/1.0/en
dc.subjectAndrogenen
dc.subjectApoptosisen
dc.subjectCastrate-resistanceen
dc.subjectChemotherapyen
dc.subjectNon-coding RNAen
dc.subjectRapalogueen
dc.titleReciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells.en
dc.typeArticleen
dc.identifier.eissn1097-0045en
dc.contributor.departmentKeele Universityen
dc.identifier.journalProstateen
dc.date.accepted2014-12-04en
or.grant.openaccessYesen
rioxxterms.funderProstate Cancer United Kingdomen
rioxxterms.identifier.projectProstate Cancer UK PA13–001en
rioxxterms.versionAMen
rioxxterms.licenseref.startdate2015-02-03en
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