Maintenance of AR Inactivation by S-nitrosylation

Hdl Handle:
http://hdl.handle.net/10675.2/559179
Title:
Maintenance of AR Inactivation by S-nitrosylation
Authors:
Qin, Yu
Abstract:
Prostate cancer is the second leading cause of cancer deaths in US men. Unregulated activation of the androgen receptor (AR) is associated with prostate cancer initiation and progression. Post-translational modifications of AR regulate its function, and we propose that nitric oxide (NO) synthase III (eNOS) and its product NO regulate prostate cancer cell growth via S-nitrosylation, a covalent addition of an NO group to a cysteine thiol, of AR. We found that S-nitrosylation levels were reduced in prostate cancer and prostatic intraepithelial neoplasia compared to normal adjacent tissues, and xD;1089-8603 (Linking)<yisbn><accession-num>15566968</accession-num><urls) Proliferation of LNCaP cells, an androgen-dependent AR-positive human prostate cancer cell line, was significantly inhibited by treatment with exogenous NO donors or overexpression of eNOS without inducing caspase 3-dependent apoptosis. In vivo experiments using tumor-bearing severe combined immunodeficient mice showed that treatment with NO donors or overexpression of eNOS significantly decreased xenografted LNCaP tumor volumes and tumor PSA levels compared to those in the control animals. Furthermore, treatment with NO donors substantially repressed androgen-independent AR-positive LNCaP-C4-2 tumor growth in vivo. These results suggest that NO may be a potential treatment option for patients diagnosed with either androgen-dependent or castration-resistant prostate cancer. Mechanistically, we found that androgen-induced AR activation was significantly inhibited in the presence of NO donors or following overexpression of eNOS in LNCaP cells, whereas reduction of eNOS levels increased AR activation. NO/eNOS had no effect on androgen-induced AR nuclear translocation; however, they substantially suppressed androgen-induced AR binding to the androgen response elements (AREs) in the promoter region of PSA. AR formed a complex with eNOS and was S-nitrosylated preferentially on cysteine 601. These results identify a new mechanism of regulating AR function in prostate cancer and form a basis for targeting S-nitrosylation of AR as a therapeutic option for treatment of patients with advanced prostate cancer.
Affiliation:
Not Listed
Issue Date:
Apr-2011
URI:
http://hdl.handle.net/10675.2/559179
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/887717826?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorQin, Yuen
dc.date.accessioned2015-07-07T20:04:32Zen
dc.date.available2015-07-07T20:04:32Zen
dc.date.issued2011-04en
dc.identifier.urihttp://hdl.handle.net/10675.2/559179en
dc.description.abstractProstate cancer is the second leading cause of cancer deaths in US men. Unregulated activation of the androgen receptor (AR) is associated with prostate cancer initiation and progression. Post-translational modifications of AR regulate its function, and we propose that nitric oxide (NO) synthase III (eNOS) and its product NO regulate prostate cancer cell growth via S-nitrosylation, a covalent addition of an NO group to a cysteine thiol, of AR. We found that S-nitrosylation levels were reduced in prostate cancer and prostatic intraepithelial neoplasia compared to normal adjacent tissues, and xD;1089-8603 (Linking)<yisbn><accession-num>15566968</accession-num><urls) Proliferation of LNCaP cells, an androgen-dependent AR-positive human prostate cancer cell line, was significantly inhibited by treatment with exogenous NO donors or overexpression of eNOS without inducing caspase 3-dependent apoptosis. In vivo experiments using tumor-bearing severe combined immunodeficient mice showed that treatment with NO donors or overexpression of eNOS significantly decreased xenografted LNCaP tumor volumes and tumor PSA levels compared to those in the control animals. Furthermore, treatment with NO donors substantially repressed androgen-independent AR-positive LNCaP-C4-2 tumor growth in vivo. These results suggest that NO may be a potential treatment option for patients diagnosed with either androgen-dependent or castration-resistant prostate cancer. Mechanistically, we found that androgen-induced AR activation was significantly inhibited in the presence of NO donors or following overexpression of eNOS in LNCaP cells, whereas reduction of eNOS levels increased AR activation. NO/eNOS had no effect on androgen-induced AR nuclear translocation; however, they substantially suppressed androgen-induced AR binding to the androgen response elements (AREs) in the promoter region of PSA. AR formed a complex with eNOS and was S-nitrosylated preferentially on cysteine 601. These results identify a new mechanism of regulating AR function in prostate cancer and form a basis for targeting S-nitrosylation of AR as a therapeutic option for treatment of patients with advanced prostate cancer.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/887717826?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectAndrogen Receptoren
dc.subjectS-nitrosylationen
dc.subjectProstate Canceren
dc.titleMaintenance of AR Inactivation by S-nitrosylationen
dc.typeDissertationen
dc.contributor.departmentNot Listeden
dc.description.advisorDaaka, Yehiaen
dc.description.committeeBollag, Wendy B.; White, Richard E.; Black, Stephen M.; Huang, Shuang; Terris, Martha K.en
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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