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Susan Ha Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA
Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA

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Rachel Ruoff Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA
Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA

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Nicole Kahoud Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA
Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA

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Thomas F Franke Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA
Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA

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Susan K Logan Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA
Departments of, Pharmacology, Urology and NYU Cancer Institute, Psychiatry, Department of Nephrology, New York University School of Medicine, 550 First Avenue, MSB424, New York, New York 10016, USA

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Multiple lines of evidence suggest a functional link between the androgen receptor (AR) and the serine/threonine kinase Akt in the development and progression of prostate cancer. To investigate the impact of Akt activity on AR homeostasis, we treated androgen-dependent LNCaP and LAPC-4 prostate cancer cells with Akt inhibitor. Akt inhibition decreased AR expression, suggesting that Akt activity was required for regulation of AR protein levels. However, while androgen-independent LNCaP-abl cells also showed diminished AR protein levels in response to Akt inhibition, treatment of androgen-independent LNCaP-AI cells failed to alter AR protein levels upon similar treatment, suggesting that AR protein levels in these androgen-independent prostate cells were regulated by mechanisms independent of Akt activation. Regulation of AR, downstream of activated Akt, also was observed in vivo when examining transgenic mice that overexpress constitutively active mutant myristoylated (myr)-Akt1 in the prostate. Transgenic mice expressing activated myr-Akt1 exhibited higher levels of AR mRNA and protein. Expression of activated myr-Akt1 did not alter prostate cell growth and no significant size differences between prostate tissues derived from transgenic animals were observed when comparing transgenic mice with wild-type mice. Still, transgenic mice overexpressing Akt exhibited higher levels of γH2AX and phosphorylated Chk2 in prostate tissue. These changes in markers associated with oncogene-induced senescence confirmed significant altered signaling in the transgenic mouse model. Overall, results presented here suggest that AR levels are regulated by the Akt pathway.

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Garrett Daniels Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Yirong Li Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Lan Lin Gellert Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Albert Zhou Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Jonathan Melamed Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Xinyu Wu Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Xinming Zhang Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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David Zhang Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Daniel Meruelo Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA
Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Susan K Logan Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA
Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA
Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Ross Basch Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Peng Lee Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA
Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA
Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA
Department of Pathology, Department of Pathology, NYU Cancer Institute, Department of Urology, Department of Pharmacology, New York Harbor Healthcare System, New York University School of Medicine, New York, New York, USA

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Androgen receptor (AR), a steroid hormone receptor, is critical for prostate cancer growth. However, activation of AR by androgens can also lead to growth suppression and differentiation. Transcriptional cofactors play an important role in this switch between proliferative and anti-proliferative AR target gene programs. Transducin β-like-related protein 1 (TBLR1), a core component of the nuclear receptor corepressor complex, shows both corepressor and coactivator activities on nuclear receptors, but little is known about its effects on AR and prostate cancer. We characterized TBLR1 as a coactivator of AR in prostate cancer cells and determined that the activation is dependent on both phosphorylation and 19S proteosome. We showed that TBLR1 physically interacts with AR and directly occupies the androgen-response elements of the affected AR target genes in an androgen-dependent manner. TBLR1 is primarily localized in the nucleus in benign prostate cells and nuclear expression is significantly reduced in prostate cancer cells in culture. Similarly, in human tumor samples, the expression of TBLR1 in the nucleus is significantly reduced in the malignant glands compared with the surrounding benign prostatic glands (P<0.005). Stable ectopic expression of nuclear TBLR1 leads to androgen-dependent growth suppression of prostate cancer cells in vitro and in vivo by selective activation of androgen-regulated genes associated with differentiation (e.g. KRT18) and growth suppression (e.g. NKX3-1), but not cell proliferation of the prostate cancer. Understanding the molecular switches involved in the transition from AR-dependent growth promotion to AR-dependent growth suppression will lead to more successful treatments for prostate cancer.

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