JOURNAL ARTICLE

Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Puralpha-mediated decrease in androgen receptor levels

Xiaomei Liu, Alejandro Gomez-Pinillos, Xiaojun Liu, Edward M Johnson, Anna C Ferrari
Prostate 2010 February 1, 70 (2): 179-89
19790234

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 (Puralpha) 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 Puralpha restored the nuclear levels and the binding of Puralpha 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 microM 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 Puralpha 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.

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