Abstract 5050: Proteome-based combined treatment strategies synergizing antagonism of androgen receptor function in prostate cancer

Abstract

Abstract Acquired resistance to second-generation androgen receptor (AR)-targeted therapies compels the development of novel therapeutic agents for castration-resistant prostate cancer (CRPC). We have recently reported a novel function of endostatin (ES) through direct binding and inhibition of AR in human prostate cancer (PCa) cells. Molecular characterization of the putative mechanisms of ES function on AR-positive PCa cells by global proteomic analysis revealed dramatic upregulation of CYP51A1 expression in LNCaP cells, suggesting that the increases in cholesterol biosynthesis and the resultant steroidogenesis may provide survival mechanism for PCa cells through the augmentation of androgen-AR axis. To validate this hypothesis, anti-proliferative effects of combined treatment of ES with Lovastatin or Fluconazole, inhibitor of HMG-CoA reductase or CYP5A1, were analyzed in vitro using AR-positive LNCaP cells. Results indicated a significantly enhanced ES-mediated growth inhibition on LNCaP cells by targeting both the ligand biosynthesis and receptor function. Proteomic profiling further indicated that ES significantly decreased the levels of AR, coactivator Ran (ARA24) and downregulated AR-driven expression of MCM complex 2, 3, 4 and 6, MDC1 and STMN1, suggesting that AR-targeted effects of ES include disruption of DNA replication, cell cycle propagation and cell division. We found that dual inhibition of AR nuclear transport and AR-mediated cell division by co-treatment of ES and Taxol greatly decreased PCa cell proliferation. Together, this interdisciplinary approach integrating proteomics with PCa cell function possibly suggests that antagonism of AR, which is the principal drug target for the PCa treatment, can be potentiated by the combination of ES with currently used chemotherapy agents and adjuvants. These findings further provide new insights into proteome-based approach as a useful tool to design and optimize effective therapeutic regimens for individual patients with CRPC. Citation Format: Joo Hyoung Lee, James A. Mobley, Selvarangan Ponnazhagan. Proteome-based combined treatment strategies synergizing antagonism of androgen receptor function in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5050. doi:10.1158/1538-7445.AM2015-5050