IL-1β induces p62/SQSTM1 and represses androgen receptor expression in prostate cancer cells

Chronic inflammation is associated with advanced prostate cancer (PCa), although the mechanisms governing inflammation-mediated PCa progression are not fully understood. PCa progresses to an androgen independent phenotype that is incurable. We previously showed that androgen independent, androgen receptor negative (AR(-) ) PCa cell lines have high p62/SQSTM1 levels required for cell survival. We also showed that factors in the HS-5 bone marrow stromal cell (BMSC) conditioned medium can upregulate p62 in AR(+) PCa cell lines, leading us to investigate AR expression under those growth conditions. In this paper, mRNA, protein, and subcellular analyses reveal that HS-5 BMSC conditioned medium represses AR mRNA, protein, and nuclear accumulation in the C4-2 PCa cell line. Using published gene expression data, we identify the inflammatory cytokine, IL-1β, as a candidate BMSC paracrine factor to regulate AR expression and find that IL-1β is sufficient to both repress AR and upregulate p62 in multiple PCa cell lines. Immunostaining demonstrates that, while the C4-2 population shows a primarily homogeneous response to factors in HS-5 BMSC conditioned medium, IL-1β elicits a strikingly heterogeneous response; suggesting that there are other regulatory factors in the conditioned medium. Finally, while we observe concomitant AR loss and p62 upregulation in IL-1β-treated C4-2 cells, silencing of AR or p62 suggests that IL-1β regulates their protein accumulation through independent pathways. Taken together, these in vitro results suggest that IL-1β can drive PCa progression in an inflammatory microenvironment through AR repression and p62 induction to promote the development and survival of androgen independent PCa.