Neamine inhibits prostate cancer growth by suppressing angiogenin-mediated rRNA transcription.
Neamine inhibits prostate cancer growth by suppressing angiogenin-mediated rRNA transcription.
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DOI：
10.1158/1078-0432.ccr-08-2593
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发表时间：
2009-03-15
期刊：
影响因子：
--
通讯作者：
Hu GF
中科院分区：
文献类型：
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作者：
Ibaragi S;Yoshioka N;Li S;Hu MG;Hirukawa S;Sadow PM;Hu GF
在前列腺癌细胞和内皮细胞中，血管生成素经历核易位并刺激核糖体RNA转录。这项研究的目的是评估neamine的抗肿瘤活性，neamine是新霉素的一种无毒降解产物，可以阻断血管生成素的核易位。neamine的抗前列腺癌活性首次在异种移植动物模型中进行了评估。然后在小鼠前列腺限制性AKT转基因小鼠（MPAKT）中检测，这些小鼠由于AKT转基因过表达而发生前列腺上皮内瘤变（PIN）。Neamine抑制胸腺小鼠PC-3人前列腺癌细胞异种移植生长。它阻断血管生成素的核易位，抑制rRNA转录，抑制细胞增殖和血管生成。Neamine还可以阻止akt诱导的PIN形成，并逆转MPAKT小鼠中完全发育的PIN，同时伴随着rRNA合成、细胞增殖和血管生成的减少，以及前列腺上皮细胞凋亡的增加。我们证实了血管生成素是癌症药物开发的分子靶点，阻断血管生成素的核易位是抑制其活性的有效手段。我们的结果还表明，奈胺是进一步临床前评估的先导化合物。
Angiogenin undergoes nuclear translocation and stimulates ribosomal RNA transcription in both prostate cancer cells and endothelial cells. The purpose of this study is to assess the anti-tumor activity of neamine, a nontoxic degradation product of neomycin that blocks nuclear translocation of angiogenin. The anti-prostate cancer activity of neamine was first evaluated in a xenograft animal model. It was then examined in the murine prostate-restricted AKT transgenic mice (MPAKT) that develop prostate intraepithelial neoplasia (PIN) owing to AKT transgene overexpression. Neamine inhibits xenograft growth of PC-3 human prostate cancer cells in athymic mice. It blocks nuclear translocation of angiogenin, inhibits rRNA transcription, cell proliferation as well as angiogenesis. Neamine also prevents AKT-induced PIN formation as well as reverses fully developed PIN in MPAKT mice, accompanied by a decrease in rRNA synthesis, cell proliferation, and angiogenesis, and an increase in prostate epithelial cell apoptosis. We confirmed that angiogenin is a molecular target for cancer drug development and that blocking nuclear translocation of angiogenin is an effective means to inhibit its activity. Our results also suggested that neamine is a lead compound for further preclinical evaluation.