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Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Purα‐mediated decrease in androgen receptor levels
Author(s) -
Liu XiaoMei,
GomezPinillos Alejandro,
Liu XiaoJun,
Johnson Edward M.,
Ferrari Anna C.
Publication year - 2009
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21051
Subject(s) - bicalutamide , androgen receptor , lncap , biology , apoptosis , cancer research , prostate cancer , flow cytometry , androgen , endocrinology , medicine , cell cycle , microbiology and biotechnology , cancer , hormone , biochemistry
BACKGROUND Increased androgen receptor (AR) levels support resistance to apoptosis and hormone therapy in advanced prostate cancer (PC). We recently linked the overexpression of AR in androgen‐independent LNCaP cells (AI‐cells) and tissues from castration‐resistant patients to decreased nuclear levels of Pur‐alpha (Purα) and loss from a protein complex bound to repressor sequences (ARS) in the 5′‐UTR of AR . Strategies to regain control of increased AR transcription may overcome resistance of AI‐cells and improve treatment outcomes. METHODS MTT, real‐time PCR, Western blot, ChIP, flow cytometry, and caspase 3/7 activation measured the effect on growth and targets of LBH589/bicalutamide treatment of AI‐cells and androgen‐dependent LNCaP cells (AD). RESULTS Within 16 hr of treatment of AI‐cells with low concentrations of the histone deacetylase inhibitor LBH589, a shift of cytoplasmic Purα restored the nuclear levels and the binding of Purα to the ARS. This was followed by a decline in AR‐mRNA and protein reaching levels of parental AD‐cells. The fraction of AI‐cells in G1 increased and the cells in S phase decreased similar to AD‐cells, and there was a modest caspase activation. Most notably, treatment of bicalutamide‐resistant AI‐cells with 10 nM LBH589 combined with 12.5 µM bicalutamide synergistically inhibited cell growth and induced a fivefold higher level of caspase 3/7 activation than observed in AD‐cells. CONCLUSIONS Low‐dose LBH589 restores Purα binding to ARS and down‐regulates AR transcription. Biologically, LBH589 reverses the resistance of AI‐cells to bicalutamide and to apoptosis. The combination may restore the hormonal response of castration‐resistant PC patients. Prostate 70: 179–189, 2010. ©2009 Wiley‐Liss, Inc.