Angiogenin mediates androgen-stimulated prostate cancer growth and enables castration resistance.
Angiogenin mediates androgen-stimulated prostate cancer growth and enables castration resistance.
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血管生成蛋白介导雄激素刺激的前列腺癌的生长，并具有cast割耐药性。
DOI：
10.1158/1541-7786.mcr-13-0072
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Hu GF
中科院分区：
文献类型：
--
作者：
Li S;Hu MG;Sun Y;Yoshioka N;Ibaragi S;Sheng J;Sun G;Kishimoto K;Hu GF
雄激素受体（AR）是前列腺癌（PCa）发生发展的重要影响因子。雄激素依赖性前列腺癌的生长和进展依赖于AR的功能。许多去势抵抗性前列腺癌继续依赖于AR信号的生存和生长。核糖体RNA （rRNA）对雄激素依赖性和去势抵抗性PCa细胞的生长都是必不可少的。在雄激素依赖性前列腺细胞生长过程中，雄激素- ar信号导致rRNA的积累。然而，AR调控rRNA转录的机制尚不清楚。我们发现血管生成素（ANG）是脊椎动物特异性分泌核糖核酸酶超家族的第5个成员，在PCa中上调，介导雄激素刺激的PCa细胞rRNA转录。雄激素刺激后，ANG在雄激素依赖性PCa细胞中发生核易位，与核糖体DNA （rDNA）启动子结合并刺激rRNA转录。在雄激素依赖性PCa细胞中，ANG拮抗剂抑制雄激素诱导的rRNA转录和细胞增殖。ANG还介导雄激素非依赖性rRNA转录。它在雄激素不敏感的PCa细胞中经历组成核易位，导致持续的rRNA过量生产，从而刺激细胞增殖。雄激素依赖性PCa细胞中ANG的过度表达使雄激素依赖性细胞的去势抗性生长。因此，ang刺激的rRNA转录不仅是PCa雄激素依赖性生长的重要组成部分，而且有助于PCa从雄激素依赖性生长状态转变为去势抗性生长状态。
Androgen receptor (AR) is a critical effector of prostate cancer (PCa) development and progression. Androgen-dependent PCa rely on the function of AR for growth and progression. Many castration-resistant PCa continue to depend on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of PCa cells. During androgen-dependent growth of prostate cells, androgen-AR signaling leads to the accumulation of rRNA. However, the mechanism by which AR regulates rRNA transcription is unknown. We have found that angiogenin (ANG), the 5th member of the vertebrate-specific, secreted ribonuclease superfamily that is upregulated in PCa, mediates androgen-stimulated rRNA transcription in PCa cells. Upon androgen stimulation, ANG undergoes nuclear translocation in androgen-dependent PCa cells where it binds to the ribosomal DNA (rDNA) promoter and stimulates rRNA transcription. ANG antagonists inhibit androgen-induced rRNA transcription and cell proliferation in androgen-dependent PCa cells. ANG also mediates androgen-independent rRNA transcription. It undergoes constitutive nuclear translocation in androgen-insensitive PCa cells, resulting in a constant rRNA overproduction thereby stimulating cell proliferation. ANG overexpression in androgen-dependent PCa cells enables castration-resistant growth of otherwise androgen-dependent cells. Thus, ANG-stimulated rRNA transcription is not only an essential component for androgen-dependent growth of PCa, but also contributes to the transition of PCa from androgen-dependent to castration-resistant growth status.