Activated checkpoint kinase 2 provides a survival signal for tumor cells
Activated checkpoint kinase 2 provides a survival signal for tumor cells
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DOI：
10.1158/0008-5472.can-06-3095
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发表时间：
2006-12-15
期刊：
影响因子：
11.2
通讯作者：
Altieri, Dario C.
中科院分区：
文献类型：
--
作者：
Ghosh, Jagadish C.;Dohi, Takehiko;Altieri, Dario C.
肿瘤细胞通常会对基于DNA损伤的治疗产生耐药性;然而，其潜在机制尚不清楚。在这里，我们表明，肿瘤细胞暴露于DNA损伤抵消细胞死亡，释放抗凋亡蛋白，生存素，从线粒体。这是独立的p53，并需要激活的检查点激酶2（Chk 2），一个假定的肿瘤抑制。Chk 2的分子或遗传靶向阻止存活素从线粒体释放，增强DNA损伤诱导的肿瘤细胞凋亡，并抑制体内耐药肿瘤的生长。因此，激活的Chk 2通过促进肿瘤细胞存活来规避其自身的肿瘤抑制功能。抑制Chk 2与DNA损伤剂的组合可能为治疗耐药肿瘤提供合理的方法。
Tumor cells often become resistant to DNA damage-based therapy; however, the underlying mechanisms are not yet understood. Here, we show that tumor cells exposed to DNA damage counteract cell death by releasing the antiapoptotic protein, survivin, from mitochondria. This is independent of p53, and requires activated checkpoint kinase 2 (Chk2), a putative tumor suppressor. Molecular or genetic targeting of Chk2 prevents the release of survivin from mitochondria, enhances DNA damage-induced tumor cell apoptosis, and inhibits the growth of resistant in vivo tumors. Therefore, activated Chk2 circumvents its own tumor-suppressive functions by promoting tumor cell survival. Inhibiting Chk2 in combination with DNA-damaging agents may provide a rational approach for treating resistant tumors.