Interleukin-1 Regulation of Androgen Receptor in Prostate Cancer


Prostate cancer (PCa) is driven by the nuclear hormone receptor, androgen receptor (AR). As such, AR is the primary treatment target for PCa. However, patients can also present with de novo loss of AR and enrichment in AR- cell types; these tumors cannot be targeted with traditional therapy, as they inherently lack the treatment target, AR. Therefore, there is need for the identification of novel therapeutic targets and characterization of the molecular switch to and/or enrichment of AR- cell types. The PCa tumor microenvironment is enriched with infiltrating immune cells that secrete inflammatory factors for the destruction and removal of tumor cells, including interleukin1 (IL-1). Unfortunately, tumor cells utilize inflammatory factors, such as IL-1, to evade cell death, metastasize, and proliferate. Previously, we have found that IL-1β represses AR accumulation and activity in AR+ PCa cells, yet an ARlow/- viable cell population remains; possibly due to the concomitant upregulation of pro-survival proteins such as p62/SQSTM1 which is basally high and necessary for the survival of AR- PCa cell types. Therefore, we sought to perform a more comprehensive study of the induced and repressed pathways that facilitate the survival of AR+ cells that lose AR in response to IL-1. In this study, we found that both IL-1 family members, IL-1α and IL-1β, either secreted from bone-derived immune cells or directly added to in vitro PCa cells, repress AR mRNA and protein accumulation and concomitantly induces pro-survival proteins and genes, such as p62, ELF3, SOX9, CD24, and CD44; and pathways such as NF- B, IL-8, and iNOS. Specifically, we have found through RNA sequencing of IL-1- treated AR+ PCa cells and AR- PCa cells that when AR+ PCa cells are treated with IL-1 there is a suite of repressed and induced genes that are basally low or high, respectively, in AR- PCa cells. Thus AR+ PCa cells may adapt to IL-1-induced AR repression and become treatment resistant by mimicking constitutive pathways found in AR- PCa cells. IL-1 is clinically relevant in both patient tissue and patient serum, negatively correlates with AR in patient tissue, and has been shown to promote PCa bone metastasis. Thus, our identification of proteins and pathways that facilitate IL-1 mediated transition of AR+ cells to AR- cells is clinically relevant. To elucidate the specific pathway by which IL-1 leads to AR repression, we pin-pointed a novel interaction between AR and the NF-B pathway protein, RELA. We performed gene silencing experiments on RELA and other NF-B family members RELB, c-REL, p50, and p52 to determine if silencing of RELA and/or other NF-B pathway interactors leads to de-repression of IL-1 mediated AR mRNA and protein repression. Indeed, silencing of RELA alone led to de-repression of AR and AR target genes in IL-1 treated AR+ cells, and subsequent downregulation of the IL-1 induced pro-survival protein p62/SQSTM1. p65(RELA) nuclear accumulation in PCa patient tissue correlates with disease recurrence and is associated with lymph node and bone metastasis. Therefore, NF-kB targeted therapy may re-sensitize some cell populations to AR-targeting therapy or could be used in combination with AR-targeting therapy in the patient setting to prevent IL-1 mediated AR loss.



Prostate -- Cancer, Interleukin-1, NF-kappa B (DNA-binding protein), Nucleotide sequence, Androgens