Identification Of A Novel Pathway Of Castrate Resistant Prostate Cancer (Crpca) Growth

Development of an effective therapy to prevent PCa occurrence, recurrence and/or progression remains an unmet medical need. This is mainly due to a poor understanding of the mechanism of PCa occurrence and progression. There is accumulating evidence that ROS (Reactive Oxygen Species) such as hydrogen peroxide, superoxide, hydroxyl radical, etc. that are produced in high amounts in PCa cells may be a major factor in PCa occurrence and its progression to androgen-independence. One of the ROS (H2O2) plays a key role in triggering growth signals and expression of transcription factors to sustain growth of androgen-dependent PCa cells in the absence of androgen. One such factor is Nuclear Factor κB (NF-κB) that may sustain cell survival by preventing apoptosis and inducing cell proliferation. NF-κB activation kinetically correlates with androgen-induced ROS production in cultured LNCaP human PCa cells. This activation is also seen in resected PCa tissues from patients, who subsequently progressed to CRPCa. Our published data show that androgen induces an up-regulation of spermidine/spermine acetyl transferase (SSAT) mRNA as well as enzyme activity that initiates polyamine oxidation in LNCaP cells after 72 h exposure. Because of the unusually high polyamine levels in the PCa cells, polyamine oxidation causes a large increase in ROS production that is abrogated by silencing SSAT expression in PCa cells stably transfected with shRNA against SSAT (siSSAT). To determine whether SSAT is required for NF-κB activation following prolonged androgen stimulus, we transfected 3xκB-luciferase vector containing NF-κB consensus binding sites-luciferase reporter construct along with a β-gal expression vector (to control for the transfection efficiency) into both wild type LNCaP cells and its siSSAT clones. While 72 h androgen exposure causes an over 30-fold induction of luciferase activity in wild type LNCaP cells, no activation of NF-κB was observed in the siSSAT clones. These data clearly show a strong SSAT induction is required for a robust activation of NF-κB in androgen-treated PCa cells. Multiple published reports show that NF-κB can also induce SSAT in several human cancer cells. Thus, our data suggest an intriguing mechanism of CRPCa progression, where androgen induced SSAT expression and consequent upregulation of NF-κB can set up an autocrine feed forward loop of SSAT-ROS-NFκB-SSAT that can sustain PCa cell proliferation in the absence of androgen that can lead to CRPCa growth. 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 2165. doi:10.1158/1538-7445.AM2011-2165