Abstract 1706: Impact of PARP1 on AR signaling and therapeutic response in prostate cancer

Abstract

Abstract Poly (ADP-ribose) polymerase 1 (PARP1) modifies various nuclear proteins by poly (ADP-ribose)-ylation, and has a known role in a multitude of chromatin-associated functions, including: transcriptional coregulation, modification of chromatin structure, regulation of insulators, and well-established activities in DNA repair. With regard to nuclear receptors, PARP1 promotes recruitment of topoisomerase IIβ (TopoIIβ) to estrogen-regulated promoters, leading to promoter DNA cleavage, factor exchange, and transcriptional activation. However, PARP1 function is known to be context dependent. Here, the impact of PARP1 on AR signaling was assessed under conditions of prostate cancer relevance. As will be discussed, key preliminary data strongly suggest that PARP1 function is critical for the pro-tumorigenic functions of AR. First, pharmacological inhibition of PARP1 enzymatic activity potently suppressed ligand-dependent AR transcriptional activity on target genes of clinical relevance. Second, the mechanism of PARP1-mediated AR regulation appears to be manifest at the level of chromatin, as inhibition of PARP1 failed to alter AR levels. This posit was assessed by chromatin immunoprecipitation assays to delineate the impact on AR signaling. Third, it was shown that suppression of PARP1 specifically inhibited AR-dependent prostate cancer cell proliferation in both early stage and late stage (castrate-resistant) models of disease. Lastly, it was observed that PARP1 inhibition cooperates with currently used genotoxic therapeutic modalities (IR and Docetaxel) in reducing cell survival, dependent on treatment scheduling. In sum, our data identify PARP1 as a critical effector of AR activity at the level of chromatin, and suggest that abrogation of PARP1 function may cooperate with existing therapeutics to improve the response to therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1706.