The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells
The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells
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DOI：
10.1158/1078-0432.ccr-07-4649
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发表时间：
2008-06-01
影响因子：
11.5
通讯作者：
Beer, Tomasz M.
中科院分区：
文献类型：
--
作者：
Myrthue, Anne;Rademacher, Brooks L. S.;Beer, Tomasz M.
1，25-二羟基维生素D-3[1，25(OH)(2)D-3]是维生素D-3最活跃的代谢物，在多种临床前癌症模型中具有显著的抗肿瘤活性。在这项研究中，我们表明，在前列腺癌患者中，1，25(OH)2D3下调了易洛魁同源盒基因5(IRX5)的表达，这些样本来自前列腺癌根治术前随机分配的每周接受高剂量1，25(OH)2D3或安慰剂的患者。1，25(OH)(2)D-3下调IRX5在人雄激素敏感的前列腺癌LNCaP细胞和雌激素敏感的MCF-7乳腺癌细胞中也被显示出来。RNA干扰下调IRX5基因后，LNCaP细胞存活率显著降低，p21蛋白表达增加，G(2)-M期阻滞，细胞凋亡率增加。诱导的细胞凋亡部分由P53介导，且IRX5基因敲除后P53蛋白表达增加。在结肠癌细胞系HCT 116和MCF-7乳腺癌细胞中，IRX5基因敲除也同样降低了细胞存活率，这两种细胞都来自似乎被1，25(OH)(2)D-3抑制的临床肿瘤类型。IRX5过表达导致p21和P53蛋白表达降低。这是首次报道IRX5在人类中受1，25(OH)(2)D-3调控，也是首次报道IRX5参与调节人前列腺癌细胞的细胞周期和细胞凋亡。IRX5有望成为肿瘤治疗的新靶点。
1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3], the most active metabolite of vitamin D-3, has significant antitumor activity in a broad range of preclinical models of cancer. In this study, we show that the Iroquois homeobox gene 5 (Irx5) is down-regulated by 1,25(OH)2D3 in human prostate cancer samples from patients randomly assigned to receive weekly high-dose 1,25(OH)2D3 or placebo before radical prostatectomy. Down-regulation of Irx5 by 1,25(OH)(2)D-3 was also shown in the human androgen -sensitive prostate cancer cell line LNCaP and in estrogen-sensitive MCF-7 breast cancer cells. Knockdown of Irx5 by RNA interference showed a significant reduction in LNCaP cell viability, which was accompanied by an increase in p21 protein expression, G(2)-M arrest, and an increase in apoptosis. The induced apoptosis was partially mediated by p53, and p53 protein expression was increased as a result of Irx5 knockdown. Cell survival was similarly reduced by Irx5 knockdown in the colon cancer cell line HCT 116 and in MCF-7 breast cancer cells, each being derived from clinical tumor types that seem to be inhibited by 1,25(OH)(2)D-3. Overexpression of Irx5 led to a reduction of p21 and p53 expression. This is the first report that Irx5 is regulated by 1,25(OH)(2)D-3 in humans and the first report to show that Irx5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells. Irx5 may be a promising new therapeutic target in cancer treatment.