Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111.
Mol Cancer Res. 2013 Oct;11(10):1203-14. doi: 10.1158/1541-7786.MCR-13-0072. Epub 2013 Jul 12.
The androgen receptor (AR) is a critical effector of prostate cancer development and progression. Androgen-dependent prostate cancer is reliant on the function of AR for growth and progression. Most castration-resistant prostate cancer (CRPC) remains dependent on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of prostate cancer 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. Here, investigation revealed that angiogenin (ANG), a member of the secreted ribonuclease superfamily, is upregulated in prostate cancer and mediates androgen-stimulated rRNA transcription in prostate cancer cells. Upon androgen stimulation, ANG undergoes nuclear translocation in androgen-dependent prostate cancer cells, where it binds to the rDNA promoter and stimulates rRNA transcription. ANG antagonists inhibit androgen-induced rRNA transcription and cell proliferation in androgen-dependent prostate cancer cells. Interestingly, ANG also mediates androgen-independent rRNA transcription through a mechanism that involves its constitutive nuclear translocation in androgen-insensitive prostate cancer cells, resulting in a constant rRNA overproduction and thereby stimulating cell proliferation. Critically, ANG overexpression in androgen-dependent prostate cancer 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 prostate cancer but also contributes to the transition of prostate cancer from androgen-dependent to castration-resistant growth status.
The ability of angiogenin to regulate rRNA transcription and prostate cancer growth makes it a viable target for therapy.
雄激素受体（AR）是前列腺癌发展和进展的关键效应因子。雄激素依赖性前列腺癌依赖 AR 功能来生长和进展。大多数去势抵抗性前列腺癌（CRPC）仍然依赖 AR 信号存活和生长。核糖体 RNA（rRNA）对前列腺癌细胞的雄激素依赖性和去势抵抗性生长都是必不可少的。在前列腺细胞的雄激素依赖性生长过程中，雄激素-AR 信号导致 rRNA 的积累。然而，AR 调节 rRNA 转录的机制尚不清楚。在这里，研究发现，血管生成素（ANG），一种分泌型核糖核酸酶超家族的成员，在前列腺癌中上调，并介导前列腺癌细胞中雄激素刺激的 rRNA 转录。在雄激素刺激下，ANG 在雄激素依赖性前列腺癌细胞中发生核易位，在那里它与 rDNA 启动子结合并刺激 rRNA 转录。ANG 拮抗剂抑制雄激素诱导的 rRNA 转录和雄激素依赖性前列腺癌细胞的增殖。有趣的是，ANG 还通过其在雄激素不敏感前列腺癌细胞中的组成型核易位来介导雄激素非依赖性 rRNA 转录，导致 rRNA 的持续过度产生，从而刺激细胞增殖。至关重要的是，ANG 在雄激素依赖性前列腺癌细胞中的过表达使原本依赖雄激素的细胞能够抵抗去势。因此，ANG 刺激的 rRNA 转录不仅是前列腺癌细胞雄激素依赖性生长的重要组成部分，而且有助于前列腺癌从雄激素依赖性向去势抵抗性生长状态的转变。
血管生成素调节 rRNA 转录和前列腺癌生长的能力使其成为治疗的可行靶点。
