Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells.
Epidemiological data on prostate cancer incidence has suggested that vitamin D deficiency may be a risk factor for prostate cancer. The antiproliferative activity of 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) and its analogues has been demonstrated in many prostate cancer models, yet the detailed mechanisms underlying this protective effect of vitamin D remain to be determined. Here, we demonstrate that two androgen receptor (AR)-positive prostate cancer cell lines, LNCaP and CWR22R, are more sensitive to the growth inhibitory effects of 1,25-VD compared to the AR-negative prostate cancer cell lines, PC-3 and DU 145. 1,25-VD treatment inhibited cyclin-dependent kinase 2 (cdk2) activity and induced G0/G1 arrest. Interestingly, we also found that 1,25-VD treatment induced the expression of AR, and that the onset of the G0/G1 arrest in LNCaP and CWR22R cells is correlated with the onset of increasing expression of AR. This implies that the antiproliferative actions of 1,25-VD in AR-positive prostate cancer might be mediated through AR. Furthermore, a reduction in 1,25-VD-mediated growth inhibition was observed when AR signaling was blocked by antiandrogens, AR RNA interference, or targeted disruption of AR. Taken together, our data suggest that the androgen/AR signaling plays an important role in the antiproliferative effects of 1,25-VD and restoration of androgen responsiveness by 1,25-VD might be beneficial for the treatment of hormone-refractory prostate cancer patients.
Bao
Bo-Ying
BY
Department of Urology, University of Rochester, Rochester, NY 14642, USA.
Hu
Yueh-Chiang
YC
Ting
Huei-Ju
HJ
Lee
Yi-Fen
YF
D000728:Androgens / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000032:analysis / Q000502:physiology; D018167:Receptors, Calcitriol / Q000502:physiology; D015398:Signal Transduction; D014105:Tosyl Compounds
D000728:Androgens; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; D014105:Tosyl Compounds; C053541:bicalutamide; D002117:Calcitriol