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Article: Functional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: Potential implications for therapeutic strategies against prostate cancer

TitleFunctional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: Potential implications for therapeutic strategies against prostate cancer
Authors
Keywordsandrogen receptor
melatonin
MT 1 receptor
p27 Kip1
prostate
Issue Date2011
PublisherBlackwell Munksgaard. The Journal's web site is located at http://www.blackwellpublishing.com/journals/JPI
Citation
Journal Of Pineal Research, 2011, v. 51 n. 3, p. 297-312 How to Cite?
AbstractRecently, a novel melatonin MT 1 receptor-mediated antiproliferative signaling mechanism involving transcriptional up-regulation of p27 Kip1 due to paralleled stimulation of protein kinase A (PKA) and protein kinase C (PKC), as a result of respective dual activation of upstream Gα s and Gα q, has been reported in 22Rv1 and RWPE-1 human prostate epithelial cells. Here, we demonstrate that melatonin inhibits the proliferation of LNCaP and VCaP prostate cancer cells via activation of the same MT 1 receptor-mediated antiproliferative signaling pathway. Knockdown of the expression of wild-type androgen receptor (AR) and/or structural/functional AR variants in LNCaP, VCaP, 22Rv1, and RWPE-1 cells resulted in abrogation of melatonin receptor-mediated antiproliferation, indicating that the antiproliferative signaling pathway MT 1/ (Gα s) PKA + (Gα q) PKC/p27 Kip1 activated by melatonin in human prostate epithelial cells is AR dependent. Furthermore, melatonin was shown to decrease androgen/AR-mediated transactivation of the prostate-specific antigen promoter in the prostate epithelial cell lines. Together, our data indicate the presence of reciprocal functional interactions between MT 1 receptor and AR signaling in malignant and nontumorigenic prostate epithelial cells. Notably, the dual actions of the MT 1 receptor-mediated antiproliferative signaling, leading to down-regulation of activated AR signaling and up-regulation of p27 Kip1, constitute the mechanistic basis for the potential use of melatonin in chemoprevention of prostate cancer, as well as in a novel therapeutic strategy, comprising a combination of melatonin repletion and androgen depletion, for the treatment of advanced or relapsed disease. © 2011 John Wiley & Sons A/S.
Persistent Identifierhttp://hdl.handle.net/10722/142504
ISSN
2015 Impact Factor: 9.314
2015 SCImago Journal Rankings: 2.655
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong Kong200907176035
Funding Information:

The authors are grateful to Dr. C. M. Perez-Stable (Veterans Affairs Medical Center, Miami, FL, USA) for the gift of PSA enhancer-promoter/luciferase reporter plasmid. This work was supported by the small project funding scheme (project code: 200907176035) of The University of Hong Kong.

References

 

DC FieldValueLanguage
dc.contributor.authorTam, CWen_HK
dc.contributor.authorShiu, SYWen_HK
dc.date.accessioned2011-10-28T02:49:26Z-
dc.date.available2011-10-28T02:49:26Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Pineal Research, 2011, v. 51 n. 3, p. 297-312en_HK
dc.identifier.issn0742-3098en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142504-
dc.description.abstractRecently, a novel melatonin MT 1 receptor-mediated antiproliferative signaling mechanism involving transcriptional up-regulation of p27 Kip1 due to paralleled stimulation of protein kinase A (PKA) and protein kinase C (PKC), as a result of respective dual activation of upstream Gα s and Gα q, has been reported in 22Rv1 and RWPE-1 human prostate epithelial cells. Here, we demonstrate that melatonin inhibits the proliferation of LNCaP and VCaP prostate cancer cells via activation of the same MT 1 receptor-mediated antiproliferative signaling pathway. Knockdown of the expression of wild-type androgen receptor (AR) and/or structural/functional AR variants in LNCaP, VCaP, 22Rv1, and RWPE-1 cells resulted in abrogation of melatonin receptor-mediated antiproliferation, indicating that the antiproliferative signaling pathway MT 1/ (Gα s) PKA + (Gα q) PKC/p27 Kip1 activated by melatonin in human prostate epithelial cells is AR dependent. Furthermore, melatonin was shown to decrease androgen/AR-mediated transactivation of the prostate-specific antigen promoter in the prostate epithelial cell lines. Together, our data indicate the presence of reciprocal functional interactions between MT 1 receptor and AR signaling in malignant and nontumorigenic prostate epithelial cells. Notably, the dual actions of the MT 1 receptor-mediated antiproliferative signaling, leading to down-regulation of activated AR signaling and up-regulation of p27 Kip1, constitute the mechanistic basis for the potential use of melatonin in chemoprevention of prostate cancer, as well as in a novel therapeutic strategy, comprising a combination of melatonin repletion and androgen depletion, for the treatment of advanced or relapsed disease. © 2011 John Wiley & Sons A/S.en_HK
dc.languageengen_US
dc.publisherBlackwell Munksgaard. The Journal's web site is located at http://www.blackwellpublishing.com/journals/JPIen_HK
dc.relation.ispartofJournal of Pineal Researchen_HK
dc.rightsThe definitive version is available at www3.interscience.wiley.com-
dc.subjectandrogen receptoren_HK
dc.subjectmelatoninen_HK
dc.subjectMT 1 receptoren_HK
dc.subjectp27 Kip1en_HK
dc.subjectprostateen_HK
dc.subject.meshCell Proliferation-
dc.subject.meshProstate - cytology - metabolism-
dc.subject.meshProstatic Neoplasms - prevention and control-
dc.subject.meshReceptors, Androgen - metabolism-
dc.subject.meshReceptors, Melatonin - physiology-
dc.titleFunctional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: Potential implications for therapeutic strategies against prostate canceren_HK
dc.typeArticleen_HK
dc.identifier.emailShiu, SYW: sywshiu@hkucc.hku.hken_HK
dc.identifier.authorityShiu, SYW=rp00384en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1111/j.1600-079X.2011.00890.xen_HK
dc.identifier.pmid21605164-
dc.identifier.scopuseid_2-s2.0-80053163223en_HK
dc.identifier.hkuros196817en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80053163223&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume51en_HK
dc.identifier.issue3en_HK
dc.identifier.spage297en_HK
dc.identifier.epage312en_HK
dc.identifier.eissn1600-079X-
dc.identifier.isiWOS:000295092400005-
dc.publisher.placeDenmarken_HK
dc.identifier.scopusauthoridTam, CW=7201442977en_HK
dc.identifier.scopusauthoridShiu, SYW=7005550655en_HK

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