Effect of androgen and natural compounds on proliferation of androgen-independent LNCaP human prostate cancer cells and prostate cancer progression

Both in vitro and in vivo, the proliferation of the androgen-independent human prostate cancer LNCaP 104-R1 and 104-R2 cells, derived from androgen-dependent 104-S cells after long-term androgen deprivation, is androgen-independent but suppressed by physiological concentration of androgen. These cells adapt to androgenic suppression, and revert to either androgen-simulated (R1Ad) or androgen-insensitive (R2Ad) state. Androgen receptor (AR) and prostate specific antigen (PSA) protein and mRNA expression level increases during progression from androgen-dependency to androgen-independency, but decreases during the adaptation to androgenic suppression. Over-expression AR allows both androgen-dependent and androgen-independent LNCaP cells be suppressed by androgen. Androgen down-regulates c-myc and skp2, and accumulates cell cycle inhibitor p27Kip1 that causes cell cycle G1 arrest but does not induce apoptosis in androgen-independent LNCaP cells. Besides, under androgen-depleted conditions, liver X receptor (LXR)-signaling is active and proliferation of androgen-dependent cells is inhibited, and the surviving androgen-independent cells escape from LXR-signaling by down-regulating LXR-related genes. (-)-epigallocatechin-3-gallate (EGCG) and caffeic acid phenethyl ester (CAPE) both have antiproliferative effect on LNCaP cells and may serve as alternative therapy for prostate cancer. Based on our results, androgen administration can be beneficial for the treatment of androgen-independent prostate cancer.