Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells
Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells
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DOI：
10.1038/sj.onc.1207461
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发表时间：
2004-04-22
期刊：
影响因子：
8
通讯作者：
Lee, YF
中科院分区：
文献类型：
--
作者：
Bao, BY;Hu, YC;Lee, YF
前列腺癌发病率的流行病学数据表明，维生素D缺乏可能是前列腺癌的危险因素。1 α，25-二羟基维生素D-3（1，25-VD）及其类似物的抗增殖活性已在许多前列腺癌模型中得到证实，但维生素D这种保护作用的详细机制仍有待确定。在这里，我们证明了两个雄激素受体（AR）阳性前列腺癌细胞系，LNCaP和CWR 22 R，是更敏感的生长抑制作用的1，25-VD相比，AR阴性前列腺癌细胞系，PC-3和DU 145。1，25-VD处理抑制细胞周期蛋白依赖性激酶2（cdk 2）活性，诱导G 0/G1期阻滞。有趣的是，我们还发现1，25-VD处理诱导AR的表达，并且LNCaP和CWR 22 R细胞中G 0/G1阻滞的开始与AR表达增加的开始相关。这意味着1，25-VD在AR阳性前列腺癌中的抗增殖作用可能通过AR介导。此外，当通过抗雄激素、AR RNA干扰或AR靶向破坏阻断AR信号传导时，观察到1，25-VD介导的生长抑制减少。综上所述，我们的数据表明，雄激素/AR信号在1，25-VD的抗增殖作用中起着重要作用，并且1，25-VD恢复雄激素反应性可能有利于治疗难治性前列腺癌患者。
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 D-3 (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.