title: IL-1β induces p62/SQSTM1 and represses androgen receptor expression in prostate cancer cells.
abstract: 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.
authors.affiliation: Department of BioSciences, Rice University, BioScience Research Collaborative, 6500 Main, MS 601, Houston, TX, 77030.
authors.forename: M A
authors.initials: MA
authors.lastname: Chang
authors.forename: V
authors.initials: V
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Gwede
authors.forename: M
authors.initials: M
authors.lastname: Morgado
authors.forename: K
authors.initials: K
authors.lastname: Tomasevich
authors.forename: E L
authors.initials: EL
authors.lastname: Fong
authors.forename: M C
authors.initials: MC
authors.lastname: Farach-Carson
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Delk
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D019899:Paracrine Communication; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053583:Interleukin-1beta; D011944:Receptors, Androgen; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: ANDROGEN RECEPTOR; BONE MARROW STROMAL CELLS; INFLAMMATION; INTERLEUKIN-1β; PROSTATE CANCER; p62/SEQUESTOME-1
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