Inhibition of Chk1 kills tetraploid tumor cells through a p53-dependent pathway.
Inhibition of Chk1 kills tetraploid tumor cells through a p53-dependent pathway.
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CHK1的抑制通过p53依赖性途径杀死四倍体肿瘤细胞。
DOI：
10.1371/journal.pone.0001337
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发表时间：
2007-12-26
期刊：
影响因子：
3.7
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Vitale, Ilio;Galluzzi, Lorenzo;Vivet, Sonia;Nanty, Lisa;Dessen, Philippe;Senovilla, Laura;Olaussen, Ken A.;Lazar, Vladimir;Prudhomme, Michelle;Golsteyn, Roy M.;Castedo, Maria;Kroemer, Guido
四倍体构成了对应激的适应以及肿瘤发生中整倍体和非整倍体之间的中间步骤。四倍体细胞特别能抵抗基因毒性应激，包括放疗和化疗。在这里，我们设计了一种优先杀死四倍体肿瘤细胞的策略。通过 siRNA 消除检查点激酶 1 (Chk1)、用显性失活 Chk1 突变体转染或药理学 Chk1 抑制可杀死四倍体结肠癌细胞，但对其二倍体对应物影响较小。 Chk1 抑制消除了纺锤体组装检查点，并导致过早和异常的有丝分裂，导致四倍体细胞中 p53 激活和细胞死亡的频率高于二倍体细胞。类似地，通过敲低 Bub1、BubR1 或 Mad2 来消除纺锤体检查点会诱导四倍体细胞的 p53 依赖性凋亡。在异种移植的人类癌症中，Chk1 抑制在体外和体内逆转了四倍体细胞的顺铂耐药性。 Chk1 抑制激活了 p53 调节的转录物，包括四倍体肿瘤细胞中的 Puma/BBC3，但在二倍体肿瘤细胞中则不然。总而言之，我们的结果表明，在四倍体肿瘤细胞中，Chk1 的抑制依次触发异常有丝分裂、p53 激活和 Puma/BBC3 依赖性线粒体凋亡。
Tetraploidy constitutes an adaptation to stress and an intermediate step between euploidy and aneuploidy in oncogenesis. Tetraploid cells are particularly resistant against genotoxic stress including radiotherapy and chemotherapy. Here, we designed a strategy to preferentially kill tetraploid tumor cells. Depletion of checkpoint kinase-1 (Chk1) by siRNAs, transfection with dominant-negative Chk1 mutants or pharmacological Chk1 inhibition killed tetraploid colon cancer cells yet had minor effects on their diploid counterparts. Chk1 inhibition abolished the spindle assembly checkpoint and caused premature and abnormal mitoses that led to p53 activation and cell death at a higher frequency in tetraploid than in diploid cells. Similarly, abolition of the spindle checkpoint by knockdown of Bub1, BubR1 or Mad2 induced p53-dependent apoptosis of tetraploid cells. Chk1 inhibition reversed the cisplatin resistance of tetraploid cells in vitro and in vivo, in xenografted human cancers. Chk1 inhibition activated p53-regulated transcripts including Puma/BBC3 in tetraploid but not in diploid tumor cells. Altogether, our results demonstrate that, in tetraploid tumor cells, the inhibition of Chk1 sequentially triggers aberrant mitosis, p53 activation and Puma/BBC3-dependent mitochondrial apoptosis.
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