Abstract 2362: NF-κB (p65) mediates interleukin-1 (IL-1) repression of androgen receptor (AR) in AR+prostate cancer (PCa) cell lines

Abstract

Inflammation promotes cancer initiation and progression. The Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells (NF-κB) family of transcription factor proteins, p65 (RelA), RelB, c-Rel, p105/p50 (NF-κB1), and p100/52 (NF-κB2), form homo- and heterodimeric complexes that mediate inflammatory cytokine signaling. We previously reported that the inflammatory cytokines, interleukin-1 alpha (IL-1α) and IL-1 beta (IL-1β), repress androgen receptor (AR) levels and activity in AR+ prostate cancer (PCa) cell lines. AR drives PCa tumorigenicity and, thus, AR is a therapeutic target. Our data suggests that IL-1 selects for ARlow/-PCa cell subpopulations that can evade AR-targeting therapy. Using RNA sequencing, we identified an IL-1-regulated gene signature predicted to supported AR-independent tumorigenicity in PCa cells. Pathway analysis of the RNA sequencing data predicted that AR is a target molecule of p65 (RELA). p50:p65 heterodimers are known to mediate IL-1 signaling, therefore, we investigated if NF-κB (p50:p65) signaling mediates IL-1 repression of AR. We found that siRNA silencing of p65 is sufficient to attenuate IL-1 repression of AR mRNA and protein levels and AR activity in AR+ PCa cell lines, while siRNA silencing of p50 had no effect on IL-1 repression of AR. Our data suggests that p65 represses AR levels, directly or indirectly, in response to IL-1. Thus, therapeutic inhibition of p65 activity could prevent the accumulation of inflammation-induced treatment-resistance ARlow/- PCa cell subpopulations. Citation Format: Shayna Elizabeth Thomas-Jardin, Haley Dahl, Monica Bautista, Freedom Ha, Joan Jacob, Afshan Fathima Nawas, Mohammed Kanshwala, Chao Xing, Nikki Delk. NF-κB (p65) mediates interleukin-1 (IL-1) repression of androgen receptor (AR) in AR+prostate cancer (PCa) cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2362.