Abstract 65: Rationally designed peptidomimetics target androgen receptor signaling in prostate cancer
Authors: Raj Ganesh V. , Ravindranathan Preethi 
Published: August 2012

INTRODUCTION AND OBJECTIVES: Androgen receptor (AR) signaling is essential for prostate cancer development, growth, and progression at all stages of disease. AR signaling occurs via both genomic and non-genomic pathways and is mediated by AR interaction with cofactors. In our laboratory, we have shown that the interaction between a cofactor, PELP1 (Proline, Glutamic acid, Leucine rich Protein 1) and AR is critical for AR nuclear translocation in response to ligand and subsequent AR-mediated genomic signaling. We hypothesized that disruption of the interaction between AR and PELP1 using rationally designed peptidomimetics could affect AR genomic signaling in prostate cancer. METHODS: We have developed rationally designed bis benzamide scaffold-based α helical peptidomimetics analogous to the LXXLL motif on PELP1 that is presumed to bind AR. Initially two peptidomimetics were created- the control D1 and a LXXLL analogue D2. Prostate cancer cell lines were pre-treated with peptidomimetics prior to incubation with androgen (DHT/R1881 (0.01-10nM)) and evaluated for proliferation. Immunofluorescence was used to examine endogenous AR translocation to the DAPI-stained nucleus. RESULTS: Initial toxicity assays using trypan blue exclusion revealed both D1 and D2 were not toxic to the cells up to 500nM concentrations. We have shown that D2 (but not the control D1) prevents the formation of the AR-PELP-1 complex as evidenced by the ability of D2 to prevent co-immunoprecipitation of AR and PELP-1 in LAPC4 and LNCaP cell lines. This effect was overcome by increased expression of either AR or PELP1. D2 was able to significantly decrease DHT-mediated transcription from both minimal ARE luciferase promoters and PSA gene expression, whereas the control D1 did not show any activity. In microarray analyses, D2 was able to abrogate the induced expression of more than 1500 of 1900 genes induced by DHT. Further, D2 was able to reduce DHT mediated proliferation of PCa cells in vitro in dose-dependent manner, whereas the control D1 did not show any activity. This ability of D2 to inhibit DHT-mediated proliferation was noted in all androgen-responsive PCa cells LAPC4, LNCaP, RWPE1, C4-2 and CWR22v1, but not PC-3 cells which lack AR expression. Interestingly, we noted that the peptidomimetic D2 blocked translocation of AR to the nucleus compared to the control D1. Finally, D2 blocked the proliferation of C4-2 sc xenografts in nude mice. CONCLUSIONS: We have shown this peptidomimetic is capable of blocking AR-PELP1 interaction, nuclear translocation of AR, AR mediated genomic signaling as well as DHT-mediated proliferation of prostate cancer cells in vitro. Selective targeting of PELP1-AR interaction affects AR genomic signaling. These data strongly indicate that this strategy may serve as a viable therapeutic target for disrupting AR function in patients with prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 65. doi:1538-7445.AM2012-65