Abstract 4383: Nrf1 and Nrf2 mediated regulation of androgen receptor signaling in androgen-independent prostate cancer cells

Abstract

Abstract Androgen deprivation is often used for the treatment of prostate cancer (PCa) patients. However, the development of androgen independent (AI) PCa remains a significant barrier to successful therapy. Interestingly, the androgen receptor (AR) is functionally expressed in all stages of PCa, although AI-PCa cells often overexpress AR and employ alternative signaling cascades to enhance AR signaling. Elevated reactive oxygen species (ROS) levels are associated with increased aggressiveness in PCa. Delineation of how these pathways are utilized by AI-PCa cells will implicate novel targets for abrogation of aggressive tumor cell growth in the later stages of PCa. We have used two sets of syngeneic PCa cell lines to emulate the progression of PCa in vitro from a non-tumorigenic stage (RWPE-1 and RWPE2 cells) to a tumorigenic and androgen-dependent (LNCaP cells) and androgen-independent (C4-2B cells) state. PSA luciferase assays showed that C4-2B cells have 7-8 fold higher activation of the AR regulated gene (PSA) than LNCaP cells after 1nM and 10nM DHT treatment for 24hrs. We have also observed that LNCaP and C4-2B cells have the ability to produce higher levels of (ROS), most likely due to an increased expression of the ROS producing enzymes, the NADPH oxidases, NOX4 and NOX5. Maintenance of higher ROS levels in C4-2B cells may allow red-ox pathways to be used for mitogenic purposes. These cells also overexpress the antioxidant proteins, Thioredoxin-1 (Trx-1) and Peroxiredoxin-1 (Prx-1), which may prevent the detrimental effects of long term exposure to ROS produced by NOX4 and NOX5. Red-ox pathways have been shown to modify hormone receptor signaling in both breast and prostate cancer. Trx-1 can differentially modulate estrogen receptor (ER) signaling in breast cancer and Prx-1 is known to bind directly to AR and enhance AR transactivation in PCa cells. The overexpression of these antioxidant proteins in AI-PCa suggests that these cells can use antioxidants to enhance AR mediated signaling, even under androgen deprived conditions. Hence, suppression of AR dependent PCa cell growth may be achieved by suppressing the induction of Prx-1 and Trx-1. Induction of these antioxidant proteins are dictated by two redox sensitive transcription factors, Nrf1 and Nrf2. C4-2B cells showed the highest expression of Nrf1 and the lowest expression of Nrf2 at the mRNA and protein levels. Indeed, decreased Nrf2 expression has also been associated with PCa aggressiveness. It is likely that a balance between Nrf1 and Nrf2 signaling regulates the expression of Prx-1 and Trx-1, which may ultimately regulate AR activity in C4-2B cells. A clearer understanding of how the Nrf1/Nrf2 balance mediates antioxidant protein expression and AR mediated gene regulation may lead to new avenues for treatment of hormone independent PCa. 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 4383.