Inflammation-mediated abrogation of androgen signaling: An in vitro model of prostate cell inflammation
Article first published online: 21 AUG 2012
© 2012 Wiley Periodicals, Inc.
Volume 53, Issue 2, pages 85–97, February 2014
How to Cite
Debelec-Butuner, B., Alapinar, C., Varisli, L., Erbaykent-Tepedelen, B., Hamid, S. M., Gonen-Korkmaz, C. and Korkmaz, K. S. (2014), Inflammation-mediated abrogation of androgen signaling: An in vitro model of prostate cell inflammation. Mol. Carcinog., 53: 85–97. doi: 10.1002/mc.21948
- Issue published online: 22 JAN 2014
- Article first published online: 21 AUG 2012
- Manuscript Accepted: 24 JUL 2012
- Manuscript Revised: 5 JUL 2012
- Manuscript Received: 12 MAY 2012
- We would like to thank Dr. R. Schneider-Stock for providing the U937 cells. This research was supported by the Turkish Scientific and Technological Research Council (grants TUBITAK-106S200, -110S134), COST action BM0703 CANGENIN (TUBITAK-108S288), and by Ege University internal funds granted to K.S.K.
- loss of p53;
- DNA damage;
As a link between inflammation and cancer has been reported in many studies, we established an in vitro model of prostatic inflammation to investigate the loss of androgen receptor (AR)-mediated signaling in androgen responsive prostate cell lines. First, the U937 monocyte cell line was differentiated into macrophages using phorbol acetate (PMA), and cells were induced with lipopolysaccharide (LPS) for cytokine secretion. Next, the cytokine levels (TNFα, IL-6, and IL1β) in conditioned media (CM) were analyzed. Prostate cells were then fed with CM containing varying concentrations of TNFα, and IkB degradation, nuclear factor kappa B (NFκB) translocation and transactivation, and the expression of matrix metalloproteinase-8 (MMP8) and matrix metalloproteinase-9 (MMP9) were then assessed. As a result of CM treatment, ubiquitin-mediated AR degradation, which was restored using anti-TNFα antibody neutralization, led to both a decrease in KLK4, PSA, and NKX3.1 expression levels and the upregulation of GPX2. In addition to the loss of AR, acute and chronic CM exposure resulted in p53 degradation and consequent p21 downregulation, which was also restored by either androgen administration or ectopic NKX3.1 expression via the stabilization of MDM2 levels in LNCaP cells. Additionally, CM treatment enhanced H2AX(S139) phosphorylation (a hallmark of DNA damage) and genetic heterogeneity in the absence of androgens in prostate cells without activating mitochondrial apoptosis. Thus, the data suggest that inflammatory cytokine exposure results in the loss of AR and p53 signaling in prostate cells and facilitates genetic heterogeneity via ROS accumulation to promote prostate carcinogenesis. © 2012 Wiley Periodicals, Inc.