Prostate cancer cells increase androgen sensitivity by increase in nuclear androgen receptor and androgen receptor coactivators; A possible mechanism of hormone-resistance of prostate cancer cells

Although androgen-hypersensitivity is one of the possible pathways of hormone-resistance in prostate cancer, the mechanisms of androgen- hypersensitivity are still largely unknown. Using androgen- hypersensitive prostate cancer cells LN-TR2, established from androgensensitive LNCaP cells by the long term treatment with tumor necrosis factor alpha, we explored the mechanisms of androgen- hypersensitivity in prostate cancer cells which may thus play a role in hormone-resistance. We examined the androgen receptor (AR) DNA sequence and the expression levels of AR and 8 AR cofactors in LNCaP and LN-TR2 cells. As a result, no novelmutation was developed in AR DNA in LN-TR2 cells. We observed higher expressions of nuclear AR upon androgen- treatment and 2 AR coactivators, ARA55 and TIF2, in LN-TR2 compared to LNCaP cells. An overexpression of ARA55 or TIF2 enhanced androgen- induced AR transcriptional activity in LNCaP cell. In the presence of those AR coactivators, AR activity was observed even at low concentrations of androgen. In 2 of 6 patients, the expression level of ARA55 was higher in cancer cells in hormone- resistant tumor than those in hormone- sensitive tumor. Taken together, our results suggest that prostate cancer cells change androgen- sensitivity by an overexpression of nuclear AR and AR coactivators, thus, resulting in transition from androgen-dependent to androgen- independent prostate cancer cells. An increase in nuclear AR and AR coactivators may cause androgen- hypersensitivity of prostate cancer cells and thus play a role in hormone- resistance, at least in some patients with prostate cancer.