A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53
A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53
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DOI：
10.1073/pnas.0813333106
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发表时间：
2009-03-10
影响因子：
11.1
通讯作者：
Papadopoulos, Nickolas
中科院分区：
文献类型：
--
作者：
Sur, Surojit;Pagliarini, Raymond;Papadopoulos, Nickolas
通过靶向同源重组，我们开发了一组匹配的结直肠癌细胞系，其差异仅在于其内源性TP 53状态。然后，我们使用这些线来定义基因的表达后，电离辐射诱导的DNA损伤改变。转录组分析显示，与野生型TP 53基因相比，TP 53基因失活的细胞中polo样激酶1（PLK 1）以及控制G2/M转换的其他基因一致上调。这导致了这样的假设，即没有WT TP 53的应激细胞的活力依赖于PLK 1。通过证明不具有WT TP 53等位基因的应激癌细胞在体内和体外对PLK 1抑制剂高度敏感来验证该假设。
Through targeted homologous recombination, we developed a panel of matched colorectal cancer cell lines that differ only with respect to their endogenous TP53 status. We then used these lines to define the genes whose expression was altered after DNA damage induced by ionizing radiation. Transcriptome analyses revealed a consistent up-regulation of polo-like kinase 1 (PLK1) as well as other genes controlling the G2/M transition in the cells whose TP53 genes were inactivated compared with those with WT TP53 genes. This led to the hypothesis that the viability of stressed cells without WT TP53 depended on PLK1. This hypothesis was validated by demonstrating that stressed cancer cells without WT TP53 alleles were highly sensitive to PLK1 inhibitors, both in vivo and in vitro.