Angiogenin-stimulated rRNA transcription is essential for initiation and survival of AKT-induced prostate intraepithelial neoplasia.
Angiogenin-stimulated rRNA transcription is essential for initiation and survival of AKT-induced prostate intraepithelial neoplasia.
复制标题
DOI：
10.1158/1541-7786.mcr-08-0137
复制
发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Hu GF
中科院分区：
文献类型：
--
作者：
Ibaragi S;Yoshioka N;Kishikawa H;Hu JK;Sadow PM;Li M;Hu GF
血管生成素(Angigenin，Ang)最初被认为是一种血管生成核糖核酸酶，最近被证明通过介导核糖体RNA(RRNA)转录而在前列腺癌细胞的增殖中发挥直接作用。Ang在人类前列腺癌中表达上调，是AKT诱导的小鼠前列腺上皮内瘤变(PIN)中最显著的上调基因。PIN病变中细胞增殖的增强需要增加核糖体的生物发生，这是一个多步骤的过程，涉及核糖体蛋白和rRNA的有序生产。已知AKT通过哺乳动物靶标雷帕霉素(MTOR)途径增强核糖体蛋白的产生。然而，目前还不清楚rRNA是如何按比例增加的。在这里，我们报告血管紧张素转换酶对于AKT驱动的PIN的形成和存活是必不可少的。我们发现，在AKT过度表达的小鼠前列腺中，Ang的上调是一个早期和持久的事件。它发生在PIN启动之前，并持续到PIN完全发展之后。通过前列腺内注射慢病毒介导的Ang特异性siRNA抑制Ang的表达，可阻止AKT诱导的PIN的形成，但不影响AKT的表达及其通过mTOR途径的信号转导。阻止Ang核转位的氨基糖苷类新霉素和Ang核糖核溶解活性的小分子酶抑制剂N65828均可预防AKT诱导的PIN形成，并逆转已建立的PIN。它们还可以减少核仁组织者区域(NOR)，恢复细胞大小，并使前列腺的管腔结构正常化，尽管AKT持续激活。三种类型的血管紧张素转换酶抑制剂均可抑制前列腺腔上皮细胞的rRNA转录，并抑制AKT诱导的PIN，提示Ang在AKT介导的细胞增殖和存活中起重要作用。
Angiogenin (ANG), originally identified as an angiogenic ribonuclease, has recently been shown to play a direct role in prostate cancer cell proliferation by mediating ribosomal RNA (rRNA) transcription. ANG is upregulated in human prostate cancer and is the most significantly upregulated gene in AKT-driven prostate intraepithelial neoplasia (PIN) in mice. Enhanced cell proliferation in the PIN lesions requires increased ribosome biogenesis, a multistep process involving an orchestrated production of ribosomal proteins and rRNA. AKT is known to enhance ribosomal protein production through the mammalian target of rapamycin (mTOR) pathway. However, it was unknown how rRNA is proportionally increased. Here, we report that ANG is essential for AKT-driven PIN formation and survival. We showed that upregulation of ANG in the AKT over-expressing mouse prostates is an early and lasting event. It occurs before PIN initiation and lasts beyond PIN is fully developed. Knocking-down ANG expression by intraprostate injection of lentivirus-mediated ANG-specific siRNA prevents AKT-induced PIN formation without affecting AKT expression and its signaling through the mTOR pathway. Neomycin, an aminoglycoside that blocks nuclear translocation of ANG, and N65828, a small-molecule enzymatic inhibitor of the ribonucleolytic activity of ANG, both prevent AKT-induced PIN formation and reverse established PIN. They also decrease nucleolar organizer region (NOR), restore cell size, and normalize luminal architectures of the prostate despite continuous activation of AKT. All three types of the ANG inhibitor suppress rRNA transcription of the prostate luminal epithelial cells and inhibit AKT-induced PIN indicating an essential role of ANG in AKT-mediated cell proliferation and survival.