Role of oxidation-triggered activation of JNK and p38 MAPK in black tea polyphenols induced apoptotic death of A375 cells
Role of oxidation-triggered activation of JNK and p38 MAPK in black tea polyphenols induced apoptotic death of A375 cells
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DOI：
10.1111/j.1349-7006.2009.01251.x
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发表时间：
2009-10-01
期刊：
影响因子：
5.7
通讯作者：
Giri, Ashok K.
中科院分区：
文献类型：
--
作者：
Bhattacharya, Udayan;Halder, Babli;Giri, Ashok K.
茶黄素(Tf)和茶红素(TR)是红茶的主要多酚类物质。我们先前的研究表明，TF和TR诱导的人恶性黑色素瘤细胞(A375)的凋亡是通过线粒体介导的途径进行的。在我们目前的研究中，我们观察了三个最重要的MAPK(ERK、JNK和p38)在Tf和TR诱导的细胞凋亡中的作用。Tf和tr处理A375细胞可持续激活JNK和p38MAPK，但不激活ERK，提示JNK和p38是多酚诱导细胞死亡的效应分子。随后的研究进一步支持了这一观点，在这些研究中，JNK和p38的激活被特定的抑制剂抑制。仅用JNK或p38特异性抑制剂处理Tf和TR处理的A375细胞死亡有明显的抑制作用。此外，我们还发现，Tf和Tr处理可诱导A375细胞内氧自由基的产生呈时间依赖性增加。有趣的是，抗氧化剂N-乙酰半胱氨酸的处理抑制了Tf和TR诱导的JNK和p38的激活以及诱导A375细胞的死亡。我们还提供了证据，证明了凋亡信号调节蛋白1在Tf和Tr诱导的A375细胞凋亡中的关键作用。综上所述，我们的结果有力地表明，Tf和Tr通过细胞内N-乙酰半胱氨酸氧化应激触发的凋亡信号调节激酶1、MAPK激酶和JNK-p38级联途径诱导A375细胞的凋亡。(《癌症科学》2009；100：1971-1978)。
Theaflavins (TF) and thearubigins (TR) are the major polyphenols of black tea. Our previous study revealed that TF- and TR-induced apoptosis of human malignant melanoma cells (A375) is executed via a mitochondria-mediated pathway. In our present study we observed the role of the three most important MAPK (ERK, JNK, and p38) in TF- and TR-induced apoptosis. TF and TR treatment of A375 cells led to sustained activation of JNK and p38 MAPK but not ERK, suggesting that JNK and p38 are the effector molecules in this polyphenol-induced cell death. This idea was further supported by subsequent studies in which JNK and p38 activation was inhibited by specific inhibitors. Significant inhibition was found in TF- and TR-treated A375 cell death pretreated with JNK- or p38-specific inhibitors only. Further, we have found that TF and TR treatment induces a time-dependent increase in intracellular reactive oxygen species generation in A375 cells. Interestingly, treatment with the antioxidant N-acetyl cystein inhibits TF- and TR-induced JNK and p38 activation as well as induction of cell death in A375 cells. We also provide evidence demonstrating the critical role of apoptosis signal-regulating kinase 1 in TF- and TR-induced apoptosis in A375 cells. Taken together our results strongly suggest that TF and TR induce apoptotic death of A375 cells through apoptosis signal-regulating kinase 1, MAPK kinase, and the JNK-p38 cascade, which is triggered by N-acetyl cystein intracellular oxidative stress. (Cancer Sci 2009; 100: 1971-1978).