Abstract 5749: Interleukin-1 (IL-1) induces a treatment-resistant gene expression pattern in prostate cancer (PCa)

Abstract

Abstract Inflammation promotes the development and progression of cancer, where inflammatory cytokines secreted by infiltrating immune cells and tumor cell autocrine signaling are usurped to promote tumor cell survival and disease progression. The interleukin-1 (IL-1) inflammatory cytokine is elevated in prostate cancer (PCa) patient tissue and serum, where it promotes PCa metastasis and bone colonization. Performing in vitro analysis on PCa cell lines and RNA sequencing, we found that IL-1 concomitantly upregulates many pro-survival and lineage proteins, and represses the hormone receptor, androgen receptor (AR). Despite AR loss, a subpopulation of PCa cells remain viable. Our observation could reflect a role for IL-1 in the de novo accumulation of AR- PCa subpopulations. Indeed, AR- PCa subpopulations, such as stem and neuroendocrine cells, are implicated in PCa resistance to AR-targeted therapies. Thus, we hypothesize that IL-1 may reprogram AR+ PCa cells into treatment-resistant AR- PCa cells that survive hormone receptor repression through the upregulation of pro-survival pathways. To begin to address this hypothesis, we performed RNA sequencing and pathway analysis to identify an IL-1-conferred expression pattern in the LNCaP AR+ PCa cell line that mimics the PC3 AR- PCa cell line. We identified canonical inflammatory and immune response pathways, including NFκB, IL-8, and iNOS signaling cascades, likely facilitating PCa cell survival in an inflammatory tumor microenvironment. We also identified novel IL-1-regulated proteins that are known to promote PCa cell survival, such as SQSTM1/p62, SOX9, and ELF3. Experiments are underway to determine the functional significance of our IL-1-conferred gene expression profile in cell line and PDX models. Our investigation will provide insight into the mechanistic function of IL-1 in PCa resistance to AR-targeted therapies Citation Format: Shayna Elizabeth Thomas-Jardin, Mohammed Kanchwala, Joan Jacob, Rachel Meade, Nagham Gahnim, Nikki Delk. Interleukin-1 (IL-1) induces a treatment-resistant gene expression pattern in prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5749.