Androgen Receptor regulation of Vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-Hydroxyvitamin D5 - a calcitriol analog.
Androgen Receptor regulation of Vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-Hydroxyvitamin D5 - a calcitriol analog.
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DOI：
10.1177/1947601910385450
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发表时间：
2010-11-16
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影响因子：
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通讯作者：
Ghosh PM
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作者：
Mooso B;Madhav A;Johnson S;Roy M;Moore ME;Moy C;Loredo GA;Mehta RG;Vaughan AT;Ghosh PM
骨化三醇（1,25(OH)2D3）对前列腺癌（CaP）具有细胞抑制作用，但由于高钙血症相关的毒性，其治疗效用有限，导致低钙化三醇类似物的发展。我们发现，1-α-羟基维生素-D5 （1α(OH)D5）可以诱导去势敏感的LNCaP前列腺癌细胞凋亡，但与骨化三醇不同，它不会增加雄激素受体（AR）的转录活性。LNCaP- ai是一种抗去势（CRCaP） LNCaP亚系，在雄激素存在下对1α(OH)D5具有抗性；然而，雄激素戒断（AWD）虽然本身无效，但却使LNCaP-AI细胞对1α(OH)D5敏感。机制研究表明，与LNCaP相比，在雄激素存在下，LNCaP- ai细胞中介导1α(OH)D5效应的维生素D受体（VDR）表达下调，而AWD则恢复了VDR的表达。由于LNCaP- ai细胞比LNCaP表达更高的AR，而AWD降低了AR，这表明VDR和AR之间存在反比关系。此外，AR刺激（通过增加雄激素）抑制VDR，而AR下调（通过ARsiRNA）刺激VDR水平，并使LNCaP- ai细胞对类似于AWD的1α(OH)D5敏感。另一种细胞系pRNS-1-1虽然是从正常前列腺中分离出来的，但在培养中失去了AR表达，并适应了不依赖雄激素的生长。这些细胞表达VDR并对1α(OH)D5敏感，但恢复AR表达抑制VDR水平并诱导对1α(OH)D5的抗性。综上所述，这些结果表明AR对CRCaP细胞中的VDR有负调控作用。这种作用可能是由禁止素（PHB）介导的，禁止素被AR转录活性抑制，并刺激CRCaP中的VDR，但不影响去势敏感细胞。因此，在去势敏感细胞中，虽然AR负性调节PHB，但这并不影响VDR的表达，而在CRCaP细胞中，AR负性调节PHB导致AR同时负性调节VDR。这些数据证明了1α(OH)D5延长CaP细胞AWD有效性的新机制。
Calcitriol (1,25(OH)2D3) is cytostatic for prostate cancer (CaP), but had limited therapeutic utility due to hypercalcemia-related toxicities, leading to the development of low-calcemic calcitriol analogs. We show that one analog, 1-α-Hydroxyvitamin-D5 (1α(OH)D5), induced apoptosis in castration-sensitive LNCaP prostate cancer cells, but unlike calcitriol, did not increase androgen receptor (AR) transcriptional activity. LNCaP-AI, a castrate-resistant (CRCaP) LNCaP subline, was resistant to 1α(OH)D5 in the presence of androgens; however, androgen withdrawal (AWD), although ineffective by itself, sensitized LNCaP-AI cells to 1α(OH)D5. Investigation of the mechanism revealed that the vitamin D receptor (VDR), which mediates the effects of 1α(OH)D5, is downregulated in LNCaP-AI cells compared to LNCaP in the presence of androgens, whereas AWD restored VDR expression. Since LNCaP-AI cells expressed higher AR compared to LNCaP and AWD decreased AR, this indicated an inverse relationship between VDR and AR. Further, AR stimulation (by increased androgen) suppressed VDR, while AR downregulation (by ARsiRNA) stimulated VDR levels and sensitized LNCaP-AI cells to 1α(OH)D5 similar to AWD. Another cell line, pRNS-1-1, although isolated from a normal prostate, had lost AR expression in culture and adapted to androgen-independent growth. These cells expressed the VDR and were sensitive to 1α(OH)D5, but restoration of AR expression suppressed VDR levels and induced resistance to 1α(OH)D5 treatment. Taken together, these results demonstrate negative regulation of VDR by AR in CRCaP cells. This effect is likely mediated by prohibitin (PHB), which was inhibited by AR transcriptional activity and stimulated VDR in CRCaP, but not castrate-sensitive cells. Therefore, in castration sensitive cells, although the AR negatively regulates PHB, this does not affect VDR expression, whereas in CRCaP cells, negative regulation of PHB by the AR results in concomitant negative regulation of the VDR by the AR. These data demonstrate a novel mechanism by which 1α(OH)D5 prolong the effectiveness of AWD in CaP cells.