Abstract A26: 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. As it is well established that AR is involved in all stages of disease, PARP inhibition could potentially serve to prevent progression. 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 protein levels. This 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. This observation could potentially lead to studies to determine if PARP inhibition can prevent the transition to castrate resistance, as there is some evidence that PARP inhibition can decrease relapse in models of mammary tumors. 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 and may serve as a means to prevent disease progression. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A26.