Selective cell death of p53-insufficient cancer cells is induced by knockdown of the mRNA export molecule GANP
Selective cell death of p53-insufficient cancer cells is induced by knockdown of the mRNA export molecule GANP
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DOI：
10.1007/s10495-012-0711-8
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发表时间：
2012-07-01
期刊：
影响因子：
7.2
通讯作者：
Sakaguchi, Nobuo
中科院分区：
文献类型：
--
作者：
Phimsen, Suchada;Kuwahara, Kazuhiko;Sakaguchi, Nobuo
癌细胞通常含有p53异常，破坏细胞周期检查点进程并导致对各种抗癌治疗的抵抗。在mRNA输出能力不足的酵母细胞中，DNA损伤发生在g1期活跃转录基因上。在这里，我们发现生发中心相关核蛋白（GANP）是酵母Sac3的同源物，参与mRNA的输出，对于确保人类基因组DNA的稳定性是必不可少的，并且GANP敲低会导致p53不足的癌细胞凋亡和坏死。Ganp小干扰RNA （siGanp）诱导的DNA损伤，伴随着s期细胞数量的减少，通过caspase依赖性和非依赖性机制导致p53缺乏的癌细胞发生晚期凋亡和坏死。在体外实验中，siGanp能有效诱导p53不足癌细胞的DNA损伤导致细胞死亡，并能保护移植到免疫功能低下小鼠体内的癌细胞的生长，提示siGanp具有选择性治疗p53不足癌细胞的潜力。
Cancer cells often contain p53 abnormalities that impair cell-cycle checkpoint progression and cause resistance to various anti-cancer treatments. DNA damage occurs at actively transcribed genes during G1-phase in yeast cells that have a deficient mRNA export capacity. Here, we show that germinal center-associated nuclear protein (GANP), a homologue of yeast Sac3 that is involved in mRNA export, is indispensable for ensuring the stability of human genomic DNA and that GANP knockdown causes apoptosis and necrosis of p53-insufficient cancer cells. Ganp small interfering RNA (siGanp)-induced DNA damage, accompanied by a decrease in the number of cells in S-phase, caused late apoptosis and necrosis in p53-insufficient cancer cells through both caspase-dependent and -independent mechanisms. siGanp effectively induced DNA damage leading to cell death in p53-insufficient cancer cells in vitro and protect the growth of cancer cells transplanted into immunocompromized mice, suggesting that siGanp has potential as a selective treatment for p53-insufficient cancer cells.