Chang, M.A.Patel, V.Gwede, M.Morgado, M.Tomasevich, K.Fong, E.L.Farach-Carson, Mary C.Delk, N.A.2014-10-092014-10-092014Chang, M.A., Patel, V., Gwede, M., et al.. "IL-1β induces p62/SQSTM1 and represses androgen receptor expression in prostate cancer cells." <i>Journal of Cellular Biochemistry,</i> 115, no. 12 (2014) John Wiley & Sons, Inc.: 2188-2197. http://dx.doi.org/10.1002/jcb.24897.https://hdl.handle.net/1911/77498Chronic 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.engThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Wiley.Journal articleInterleukin-1βp62/Sequestome-1androgen receptorprostate cancerbone marrow stromal cellsinflammationhttp://dx.doi.org/10.1002/jcb.24897