Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells
Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells
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DOI：
10.1038/cr.2008.86
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发表时间：
2008-08-01
期刊：
影响因子：
44.1
通讯作者：
Li, Wen Xin
中科院分区：
文献类型：
--
作者：
Mao, Xin;Yu, Chun Rong;Li, Wen Xin
本研究探讨了紫草素诱导Bcr/ abl阳性慢性髓性白血病（CML）细胞（如K562， LAMA84）凋亡的信号转导事件。用紫草素（如0.5 μ M）处理K562细胞，可显著诱导细胞凋亡，同时快速生成活性氧（ROS），显著激活c- jun - n末端激酶（JNK）和p38，显著释放线粒体蛋白细胞色素c和Smac/DIABLO，激活caspase-9和-3，并裂解PAR-P。清除ROS完全阻断了紫草素处理后的上述所有事件（即JNK和p38磷酸化、细胞色素c和Smac/DIABLO释放、caspase和PARP切割以及诱导凋亡）。JNK的抑制和JNK1的敲除显著降低了细胞色素c的释放、caspase的裂解和凋亡，但不影响紫草素介导的ROS的产生。此外，抑制caspase激活完全阻断了紫草素诱导的细胞凋亡，但没有明显改变紫草素介导的细胞色素c释放或ROS生成。总之，这些发现表明，紫草素诱导的氧化损伤在凋亡信号级联反应的近端点起作用，随后激活应激相关的JNK通路，触发线粒体功能障碍、细胞色素c释放和caspase激活，并导致细胞凋亡。我们的数据还表明，紫草素可能是治疗CML的一种有前景的药物，作为ROS的发生器。
This study examined the signaling events induced by shikonin that lead to the induction of apoptosis in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells (e.g., K562, LAMA84). Treatment of K562 cells with shikonin (e.g., 0.5 mu M) resulted in profound induction of apoptosis accompanied by rapid generation of reactive oxygen species (ROS), striking activation of c-Jun-N-terminal kinase (JNK) and p38, marked release of the mitochondrial proteins cytochrome c and Smac/DIABLO, activation of caspase-9 and -3, and cleavage of PAR-P. Scavenging of ROS completely blocked all of the above-mentioned events (i.e., JNK and p38 phosphorylation, cytochrome c and Smac/DIABLO release, caspase and PARP cleavage, as well as the induction of apoptosis) following shikonin treatment. Inhibition of JNK and knock-down of JNK1 significantly attenuated cytochrome c release, caspase cleavage and apoptosis, but did not affect shikonin-mediated ROS production. Additionally, inhibition of caspase activation completely blocked shikonin-induced apoptosis, but did not appreciably modify shikonin-mediated cytochrome c release or ROS generation. Altogether, these findings demonstrate that shikonin-induced oxidative injury operates at a proximal point in apoptotic signaling cascades, and subsequently activates the stress-related JNK pathway, triggers mitochondrial dysfunction, cytochrome c release, and caspase activation, and leads to apoptosis. Our data also suggest that shikonin may be a promising agent for the treatment of CML, as a generator of ROS.