Abstract 1713: Activation of the aryl hydrocarbon receptor and down-regulation of the androgen receptor in prostate cancer cells by the curcumin analog C48

The androgen receptor (AR) is a critical player in prostate cancer (CaP) development and progression and is a well-established therapeutic target. Recent studies have shown the aryl hydrocarbon receptor (AhR) is an important modulator of the AR acting as an adaptor for ubiquitin ligases and increasing the degradation of the AR. The natural product curcumin, a known inhibitor of the AR, has been shown to modulate the activity of the AhR. We have identified a curcumin analog, C48, which potently inhibits CaP cell proliferation. The purpose of this study was to identify molecular pathways that contribute to the effects of C48 on CaP cells, which may involve AR down-regulation through an AhR-mediated mechanism. Androgen-sensitive LAPC4, LNCaP and C4-2 CaP cells were used to perform these studies. We have found that C48 potently reduces AR expression levels in CaP cells in a dose- and time-dependent manner. C48 also decreased expression of genes induced by the AR, such as prostate specific antigen. We have found that a potent AhR activator, benzo(a)pyrene, down-regulates AR protein expression in CaP cells. As with benzo(a)pyrene, C48 was found to activate the AhR as determined using an AhR-activated reporter system. In addition, C48 potently induced markers of AhR activation including cytochrome P450 1A1 and aldoketoreductase 1C1 in CaP cells. Previous studies (e.g., Fritz et al., 2007) have shown that the AhR may act as a prostate cancer suppressor. Results from this study may facilitate the identification of safe and effective agents, such as the curcumin analog C48, that target AR down-regulation as a potential therapeutic strategy for prostate cancer without the toxicities associated with agents such as benzo(a)pyrene. 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 1713.