Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.
Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.
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DOI：
10.1677/jme-07-0158
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发表时间：
2008-07
影响因子：
3.5
通讯作者：
C. Hsieh;Changmeng Cai;Ahmed Giwa;A. Bivins;Shaoyong Chen;D. Sabry;K. Govardhan;L. Shemshedini
中科院分区：
文献类型：
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作者：
C. Hsieh;Changmeng Cai;Ahmed Giwa;A. Bivins;Shaoyong Chen;D. Sabry;K. Govardhan;L. Shemshedini
影响雄激素受体（AR）的细胞变化可导致前列腺癌从雄激素依赖性转变为雄激素非依赖性，这通常是致命的。前列腺肿瘤中的一个常见变化是AR的过度表达，这已被证明会导致前列腺癌细胞的雄激素非依赖性生长。这使我们假设过度活跃的AR的表达足以使前列腺癌细胞的雄激素非依赖性生长。为了检验这一假设，产生了稳定的肺癌前列腺（LNCaP）细胞系，其表达病毒体磷蛋白（VP）16-AR杂合蛋白，所述杂合蛋白含有与强病毒转录激活结构域VP 16融合的全长AR。这种融合蛋白引起的转录活性比天然AR强20倍。VP 16-AR在LNCaP细胞中的稳定表达产生了雄激素非依赖性细胞增殖，而在相同的生长条件下，亲本LNCaP细胞仅表现出雄激素依赖性生长。这些结果表明，高活性AR的表达足以使前列腺癌细胞的雄激素非依赖性生长。为了研究这种增强生长的分子基础，我们测量了可溶性鸟苷酸环化酶-α 1（sGCalpha 1）的表达，sGC是一种雄激素调节基因，已被证明参与前列腺癌细胞生长。有趣的是，sGCalpha 1的表达在VP 16-AR表达细胞中是雄激素非依赖性的，与其在对照LNCaP细胞中的雄激素诱导的表达相反。RNA（I）依赖性抑制sGCalpha 1表达导致VP 16-AR细胞增殖显著降低，暗示sGCalpha 1在这些细胞的雄激素非依赖性生长中起重要作用。
Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.