c-Jun NH2-terminal kinase signaling axis regulates diallyl trisulfide-induced generation of reactive oxygen species and cell cycle arrest in human prostate cancer cells
c-Jun NH2-terminal kinase signaling axis regulates diallyl trisulfide-induced generation of reactive oxygen species and cell cycle arrest in human prostate cancer cells
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DOI：
10.1158/0008-5472.can-06-0356
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Singh, Shivendra V.
中科院分区：
文献类型：
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作者：
Antosiewicz, Jedrzej;Herman-Antosiewicz, Anna;Singh, Shivendra V.
我们以前已经表明，活性氧（ROS）的产生是由二烯丙基三硫化物（DATS），这是一个非常有前途的抗癌成分加工大蒜引起的G2-M期细胞周期停滞的关键事件。使用DU 145和PC-3人前列腺癌细胞作为模型，我们现在报告了一种新的机制，涉及c-Jun NH 2-末端激酶（JNK）信号轴，这是已知的调节细胞存活和凋亡的作用，在DATS诱导的ROS产生。在EUK 134（一种超氧化物歧化酶和过氧化氢酶的组合模拟物）的存在下，DATS诱导的ROS产生、G2-M期细胞周期停滞和降解以及Cdc 25 C的过度磷酸化显著减弱。有趣的是，在去铁胺（一种铁螯合剂）的存在下，DATS诱导的ROS产生和G2-M期细胞周期阻滞也被显著抑制，但在铁饱和的去铁胺中没有观察到这种保护作用。DATS处理引起不稳定铁水平的显着增加，伴随着铁储存蛋白铁蛋白轻链的降解。有趣的是，DATS介导的铁蛋白降解，增加不稳定的铁池，活性氧的产生，和/或细胞周期停滞显着减弱的异位表达的JNK激酶2的催化失活突变体和RNA干扰的应激活化蛋白激酶/细胞外信号调节激酶1（SEK 1），上游激酶在JNK信号转导途径。总之，本研究提供了实验证据，表明存在一个新的途径，涉及JNK信号轴调节DATS诱导的ROS的产生。
We have shown previously that generation of reactive oxygen species (ROS) is a critical event in G2-M phase cell cycle arrest caused by diallyl trisulfide (DATS), which is a highly promising anticancer constituent of processed garlic. Using DU145 and PC-3 human prostate cancer cells as a model, we now report a novel mechanism involving c-Jun NH2-terminal kinase (JNK) signaling axis, which is known for its role in regulation of cell survival and apoptosis, in DATS-induced ROS production. The DATS-induced ROS generation, G2-M phase cell cycle arrest and degradation, and hyperphosphorylation of Cdc25C were significantly attenuated in the presence of EUK134, a combined mimetic of superoxide dismutase and catalase. Interestingly, the DATS-induced ROS generation and G2-M phase cell cycle arrest were also inhibited significantly in the presence of desferrioxamine, an iron chelator, but this protection was not observed with iron-saturated desferrioxamine. DATS treatment caused a marked increase in the level of labile iron that was accompanied by degradation of light chain of iron storage protein ferritin. Interestingly, DATS-mediated degradation of ferritin, increase in labile iron pool, ROS generation, and/or cell cycle arrest were significantly attenuated by ectopic expression of a catalytically inactive mutant of JNK kinase 2 and RNA interference of stress-activated protein kinase/extracellular signal-regulated kinase 1 (SEK1), upstream kinases in JNK signal transduction pathway. In conclusion, the present study provides experimental evidence to indicate existence of a novel pathway involving JNK signaling axis in regulation of DATS-induced ROS generation.