Androgen Receptor Requires JunD as a Co-activator to Switch on an Oxidative Stress Generation Pathway in Prostate Cancer Cells

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The relatively high oxidative stress in the prostate is postulated to be one of the major factors for prostate carcinogenesis and prostate cancer (CaP) progression. We focused on elucidating metabolic pathways of oxidative stress generation in CaP cells. Previously, we have shown that the transcription factor JunD is essential for the androgen-induced reactive oxygen species (ROS) production in androgen-dependent LNCaP human prostate cancer cells. We have also recently demonstrated that androgen induces the first and the regulatory enzyme spermidine/spermine N1-acetyl transferase (SSAT) in a polyamine catabolic pathway that produces copious amounts of metabolic ROS. Here, we present co-immunoprecipitation and Gaussia luciferase reconstitution assay data that show that JunD forms a complex with activated AR in situ. Our chromatin immnoprecipitation (ChIP) assay data demonstrate that JunD binds directly with a specific SSAT promoter sequence only in androgen-treated LNCaP cells. Using a vector containing a luciferase reporter gene connected to the SSAT promoter and a JunD silenced LNCaP cell line, we show that JunD is an essential co-activator of androgen-induction of SSAT gene expression. As there is no Androgen Response Element (ARE) in the SSAT promoter, we hypothesize that JunD mediates binding of androgen-activated AR to the SSAT promoter for the induction of SSAT that leads to polyamine oxidation and ROS production in prostate cells. Elucidation of this pathway may help the design of inhibitors of oxidative stress generation specifically in prostate cells to prevent prostate cancer occurrence and progression. 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 4386.