Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor

Boyu Zhang, Oh Joon Kwon, Gervaise Henry, Alicia Malewska, Xing Wei, Li Zhang, William Brinkley, Yiqun Zhang, Patricia D. Castro, Mark Titus, Rui Chen, Mohammad Sayeeduddin, Ganesh Raj, Ryan Mauck, Claus Roehrborn, Chad J. Creighton, Douglas W Strand, Michael M. Ittmann, Li Xin

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31 Scopus citations

Abstract

Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases.

Original languageEnglish (US)
Pages (from-to)976-989
Number of pages14
JournalMolecular Cell
Volume63
Issue number6
DOIs
StatePublished - Sep 15 2016

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Keywords

  • androgen receptor
  • benign prostatic hyperplasia
  • epithelial homeostasis
  • inflammation
  • interleukin-1
  • macrophage
  • microenvironment

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Zhang, B., Kwon, O. J., Henry, G., Malewska, A., Wei, X., Zhang, L., Brinkley, W., Zhang, Y., Castro, P. D., Titus, M., Chen, R., Sayeeduddin, M., Raj, G., Mauck, R., Roehrborn, C., Creighton, C. J., Strand, D. W., Ittmann, M. M., & Xin, L. (2016). Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor. Molecular Cell, 63(6), 976-989. https://doi.org/10.1016/j.molcel.2016.07.025