β-Lapachone Significantly Increases the Effect of Ionizing Radiation to Cause Mitochondrial Apoptosis via JNK Activation in Cancer Cells
β-Lapachone Significantly Increases the Effect of Ionizing Radiation to Cause Mitochondrial Apoptosis via JNK Activation in Cancer Cells
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DOI：
10.1371/journal.pone.0025976
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发表时间：
2011-10-06
期刊：
影响因子：
3.7
通讯作者：
Park, Heon Joo
中科院分区：
文献类型：
--
作者：
Park, Moon-Taek;Song, Min-Jeong;Park, Heon Joo
背景资料：已知β-拉帕醌（β-lap）引起癌细胞中NQO 1依赖性死亡并使癌细胞对电离辐射（IR）敏感。我们研究了beta-lap引起的放射增敏的机制。方法学/主要发现：beta-lap增强了IR在NQO 1（+）-MDA-MB-231细胞中引起克隆形成细胞的作用，但在NQO 1（-）-MDA-MB-231细胞中不增强。β-lap仅在NQO 1（+）细胞中引起凋亡，而在NQO 1（-）细胞中不引起凋亡，并且仅在NQO 1（+）细胞中显著增加IR诱导的凋亡。联合处理NQO 1（+）细胞可诱导ROS产生，触发ER应激，刺激ERK和JNK活化。NAC抑制ROS的产生有效地减弱了ERK和JNK的激活，ER应激的诱导，以及随后的凋亡。重要的是，ERK的抑制消除了ROS的产生和ER应激，而JNK的抑制则没有，这表明ERK激活和ROS产生之间的正反馈调节触发了对联合治疗的响应的ER应激。此外，ER应激的预防完全阻断了联合治疗诱导的JNK激活和随后的细胞凋亡。此外，联合治疗有效地诱导线粒体易位的切割Bax，破坏线粒体膜电位，和核转位的AIF，所有这些都有效地阻断JNK抑制剂。半胱天冬酶3，8和9被激活的联合治疗，但这些半胱天冬酶的抑制并没有取消细胞凋亡，表明半胱天冬酶的激活在诱导apoptosis.Conclusions/Significance：β-lap导致NQO 1依赖的放射增敏的癌细胞中发挥了次要作用。当用IR和β-lap组合处理NQO 1（+）细胞时，ERK和ROS之间的正反馈调节导致ER应激，引起JNK活化和切割的Bax的线粒体易位。线粒体膜的减少导致AIF易位和细胞凋亡。
Background: beta-lapachone (beta-lap), has been known to cause NQO1-dependnet death in cancer cells and sensitize cancer cells to ionizing radiation (IR). We investigated the mechanisms underlying the radiosensitization caused by beta-lap.Methodology/Principal Findings: beta-lap enhanced the effect of IR to cause clonogenic cells in NQO1(+)-MDA-MB-231 cells but not in NQO1(-)-MDA-MB-231 cells. beta-lap caused apoptosis only in NQO1(+) cells and not in NQO1(-) cells and it markedly increased IR-induced apoptosis only in NQO1(+) cells. Combined treatment of NQO1(+) cells induced ROS generation, triggered ER stress and stimulated activation of ERK and JNK. Inhibition of ROS generation by NAC effectively attenuated the activation of ERK and JNK, induction of ER stress, and subsequent apoptosis. Importantly, inhibition of ERK abolished ROS generation and ER stress, whereas inhibition of JNK did not, indicating that positive feedback regulation between ERK activation and ROS generation triggers ER stress in response to combined treatment. Furthermore, prevention of ER stress completely blocked combination treatment-induced JNK activation and subsequent apoptotic cell death. In addition, combined treatment efficiently induced the mitochondrial translocation of cleaved Bax, disrupted mitochondrial membrane potential, and the nuclear translocation of AIF, all of which were efficiently blocked by a JNK inhibitor. Caspases 3, 8 and 9 were activated by combined treatment but inhibition of these caspases did not abolish apoptosis indicating caspase activation played a minor role in the induction of apoptosis.Conclusions/Significance: beta-lap causes NQO1-dependent radiosensitization of cancer cells. When NQO1(+) cells are treated with combination of IR and beta-lap, positive feedback regulation between ERK and ROS leads to ER stress causing JNK activation and mitochondrial translocation of cleaved Bax. The resultant decrease in mitochondrial membrane leads to translocation of AIF and apoptosis.