RRC ID 34790
Author Kim YC, Chen C, Bolton EC.
Title Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells.
Journal PLoS ONE
Abstract The androgen receptor (AR) mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT). However, the mechanisms whereby AR regulates growth suppression and differentiation 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 development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR), and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK) complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation.
Volume 10(9)
Pages e0138286
Published 2015
DOI 10.1371/journal.pone.0138286
PII PONE-D-14-27114
PMID 26372468
PMC PMC4570807
MeSH Androgens / pharmacology Cell Cycle Checkpoints / drug effects Cell Line Cell Proliferation / drug effects Cyclin D1 / genetics Cyclin D1 / metabolism Cyclin D2 / genetics Cyclin D2 / metabolism Cyclin-Dependent Kinase 4 / genetics Cyclin-Dependent Kinase 4 / metabolism Cyclin-Dependent Kinase 6 / genetics Cyclin-Dependent Kinase 6 / metabolism Cyclin-Dependent Kinase Inhibitor p21 / genetics Cyclin-Dependent Kinase Inhibitor p21 / metabolism Epithelial Cells / cytology* Epithelial Cells / drug effects Epithelial Cells / metabolism* Gene Expression Regulation / drug effects Humans Male Prostate / cytology* RNA Stability / drug effects RNA, Messenger / chemistry RNA, Messenger / genetics RNA, Messenger / metabolism Receptors, Androgen / metabolism* Signal Transduction / drug effects Transcription, Genetic / drug effects
IF 2.766
Times Cited 1
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material CSII-EF-MCS (RDB04378)