Chemical ablation of androgen receptor in prostate cancer cells with the histone deacetylase inhibitor LAQ824

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After the initial response to androgen deprivation therapy, prostate cancer usually relapses to the hormone-refractory (androgen-independent) disease. Significantly, most hormone-refractory prostate cancer cells still express AR. Accumulated evidence suggests that reactivation of AR through mutations, overexpression, posttranslational modification of the receptor or its co-activators is a major mechanism responsible for progression of androgen-sensitive prostate cancer to the hormone-refractory state. Therefore, ablation of AR from prostate cancer cells is an attractive concept for developing a new therapy for both androgen-dependent as well as hormone-refractory prostate cancer. The stability and maturation of AR depend on the Hsp90 molecular chaperone activity. We have found that LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor (HDI) currently in human clinical trials, effectively depleted AR in prostate cancer cells at nanomolar concentrations. Several lines of evidence suggest that LAQ824 depleted AR by inactivating the Hsp90 molecular chaperone. First, besides AR, LAQ824 reduced the levels of Hsp90 client proteins HER-2, Akt/PKB, and Raf-1 in LNCaP prostate cancer cells. Second, another Hsp90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), also induced AR diminution. Third, LAQ824 induced Hsp90 acetylation in LNCaP cells, which resulted in inhibition of its ATP binding activity, dissociation of Hsp90-AR complex, and proteasome-mediated degradation of AR. Consequently, LAQ824 blocked androgen-induced prostate specific antigen (PSA) production in LNCaP cells. LAQ824 effectively inhibited cell proliferation and induced apoptosis of prostate cancer cells. These results reveal that LAQ824 and other HDIs that can inhibit Hsp90 are effective agents for depletion of AR from prostate cancer cells and are potential new drugs for prostate cancer.