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Title:Androgen receptor-mediated growth suppression and apoptosis of human prostate epithelial cells
Author(s):Chen, Congcong
Director of Research:Bolton, Eric C.
Doctoral Committee Chair(s):Bolton, Eric C.
Doctoral Committee Member(s):Bagchi, Milan K.; Katzenellenbogen, Benita S.; Shapiro, David J.
Department / Program:Molecular & Integrative Physi
Discipline:Molecular & Integrative Physi
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Androgen Receptor
Prostate Cancer
Growth Suppression
Cell Cycle
Cell Death
Abstract:Androgen receptor (AR) signaling is crucial to the development, growth, and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies, including benign and malignant forms of neoplasia. Prostate cancer is the second most prevalent cancer and the sixth leading cause of cancer mortality in men. The mechanisms whereby AR regulates growth suppression and survival/death of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate growth, homeostasis, and neoplasia. We hypothesized that in normal adult prostate, AR signaling may serve homeostatic roles in the regulation of cell cycle progression and programmed cell death such that it restrains the growth of healthy epithelial cells and accelerates the turnover of damaged epithelial cells. To test this hypothesis, we examined the growth/apoptosis response of human prostate epithelial cell lines (HPr-1AR, RWPE-AR and PC3-Lenti-AR) under optimized or stressed conditions, identified androgen-responsive genes that restrain cell cycle progression or mediate programmed cell death, and defined mechanisms whereby AR regulates their expression. Here, we report the mechanisms of AR-mediated growth suppression and AR-sensitized apoptotic cell death in these prostate epithelial cell lines. Under optimized culture conditions, AR signaling inhibits the proliferation of HPr-1AR and PC3-Lenti-AR cells, but does not induce cell death. AR-mediated growth suppression is dependent on the inhibition of cyclin D-CDK4/6 complexes through transcriptional repression of the CDK4 and CDK6 genes and transcriptional activation of the CDKN1A/p21 gene. Further, AR inhibits cyclin D2 transcription and destabilizes cyclin D1 mRNA in HPr-1AR cells. The decreased expression and activity of cyclin D-CDK4/6 complexes lead to a prolonged G0/G1 interval and, therefore, restrains cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR. Under stressed culture conditions, AR signaling sensitizes HPr-1AR and RWPE-AR cells to apoptotic cell death. Co-treatment of these cells with androgen and a cell stress agent, such as staurosporine (STS) or TNFα, synergistically increases apoptotic cell death in comparison to treatment with cell stress agent alone. The synergy between androgen and stress inducer is dependent on AR and transcription and involves the activation of the intrinsic mitochondrial apoptotic pathway. Expression analyses reveal that pro-apoptotic genes (BCL2L11/BIM, BOK and AIFM2) are androgen-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) are androgen-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins in a manner that sensitizes mitochondria to apoptotic signaling and thus renders HPr-1AR more vulnerable to cell stress agents. These studies provide novel insights into the homeostatic roles of AR in the regulation of prostate epithelial cell proliferation and turnover.
Issue Date:2016-11-28
Rights Information:Copyright 2016 Congcong Chen
Date Available in IDEALS:2017-03-01
Date Deposited:2016-12

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