Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation
Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation
复制标题
DOI：
10.1038/sj.onc.1209956
复制
发表时间：
2007-03-08
期刊：
影响因子：
8
通讯作者：
Shemshedini, L.
中科院分区：
文献类型：
--
作者：
Cai, C.;Chen, S-Y;Shemshedini, L.
前列腺癌的生长和进展依赖于雄激素和雄激素受体（AR），其通过调节基因表达起作用。利用基因芯片的方法，我们已经确定了可溶性鸟苷酸环化酶（sGC）的α 1-亚基基因作为一种新的雄激素调节基因。sGC是一种由一个α和一个β亚基组成的异二聚体细胞质蛋白，介导一氧化氮（NO）的广泛细胞效应。我们在这里报告，在前列腺癌细胞中，雄激素刺激sGC α 1的表达。克隆的人sGC α 1启动子被雄激素以AR依赖的方式激活，表明sGC α 1可能是直接的AR靶基因。sGC α 1表达的破坏严重损害了雄激素依赖性和雄激素非依赖性AR阳性前列腺癌细胞的生长。sGC α 1单独过表达足以刺激前列腺癌细胞增殖。有趣的是，sGC α 1的主要生长效应不依赖于NO和环鸟苷一磷酸，环鸟苷一磷酸是sGC酶的主要介质。这些数据强烈表明，sGC α 1通过一种不依赖于sGC β 1的新途径在前列腺癌中起作用。组织研究表明，sGC α 1表达在晚期前列腺癌中显著升高。因此，sGC α 1可能是雄激素致癌作用的重要介质。
The growth and progression of prostate cancer are dependent on androgens and androgen receptor (AR), which act by modulating gene expression. Utilizing a gene microarray approach, we have identified the alpha 1-subunit gene of soluble guanylyl cyclase (sGC) as a novel androgen-regulated gene. A heterodimeric cytoplasmic protein composed of one alpha and one beta subunit, sGC mediates the widespread cellular effects of nitric oxide (NO). We report here that, in prostate cancer cells, androgens stimulate the expression of sGC alpha 1. A cloned human sGC alpha 1 promoter is activated by androgen in an AR-dependent manner, suggesting that sGC alpha 1 may be a direct AR target gene. Disruption of sGC alpha 1 expression severely compromises the growth of both androgen-dependent and androgen-independent AR-positive prostate cancer cells. Overexpression of sGC alpha 1 alone is sufficient for stimulating prostate cancer cell proliferation. Interestingly, the major growth effect of sGC alpha 1 is independent of NO and cyclic guanosine monophosphate, a major mediator of the sGC enzyme. These data strongly suggest that sGC alpha 1 acts in prostate cancer via a novel pathway that does not depend on sGC beta 1. Tissue studies show that sGC alpha 1 expression is significantly elevated in advanced prostate cancer. Thus, sGC alpha 1 may be an important mediator of the procarcinogenic effects of androgens.