Abstract 2073: Curcumin analog 27 induced reactive oxygen species mediate loss of androgen receptor protein expression in human prostate cancer cells

Abstract

Abstract The androgen receptor (AR) is an established therapeutic target for prostate cancer. Therefore, agents that down-regulate AR expression may be effective for prostate cancer therapy. We show that the experimental therapeutic agent, curcumin analog 27 (ca27), induces the down-regulation of the AR in LNCaP and LAPC4 prostate cancer cell lines. Treatment with ca27 selectively inhibits AR mRNA expression, whereas ca27 did not alter mRNA levels for other steroid hormone receptors, such as the glucocorticoid receptor. In addition, ca27 decreases AR protein expression and increases AR protein ubiquitination within 3 hours. However, this rapid decrease in AR protein expression by ca27 is not mediated by proteasomal degradation. Interestingly, we observed an induction of reactive oxygen species (ROS) within 1 to 2 hours of ca27 treatment, which precedes AR degradation, leading to the hypothesis that ca27 mediates AR degradation through a cellular oxidative stress mechanism of action. In support of this hypothesis, the degradation of the AR following ca27 treatment is abrogated in the presence of the antioxidant, N-acetyl cysteine. Treatment with ca27 did not reduce cell viability by 24 hours suggesting that the increase in ROS and the inhibition of AR protein expression are independent of cell death. To further evaluate the cellular response to oxidative stress by ca27, we investigated the induction of a critical transcription factor activated as a cellular redox sensor, Nrf2. Treatment with ca27 lead to the increased transcriptional activation of Nrf2 as measured by an Nrf2-luciferase reporter assay. The ca27-induced Nrf2 activation was further supported by increased mRNA expression of the Nrf2-regulated genes NAD(P)H quinone oxidoreductase 1 and aldoketoreductase 1C1. This study begins to identify the mechanism of action of ca27-mediated AR protein degradation with the overall goal of gaining insight into targeting ROS-mediated AR down-regulation as a strategy for prostate cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2073. doi:10.1158/1538-7445.AM2011-2073