Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu, Korea.
J Pineal Res. 2011 May;50(4):359-66. doi: 10.1111/j.1600-079X.2010.00851.x. Epub 2011 Jan 18.
Melatonin has recently gained attention as a regulator of biologic processes in addition to its effects on circadian rhythms. The mechanisms whereby melatonin regulates the apoptotic program remain poorly understood. In this study, we investigated the combined effect of melatonin and kahweol on apoptosis of cancer cells, but not in most normal human cell types, thus presenting an attractive novel strategy for cancer treatment. In our experiments, treatment with a combination of melatonin and kahweol induced apoptosis, stimulated DEVDase activity, and DNA fragmentation. Co-treatment with melatonin and kahweol induced up-regulation of p53-upregulated modulator of apoptosis (PUMA) while down-regulation of PUMA expression using small interfering RNAs attenuated melatonin plus kahweol-induced apoptosis. In addition, co-treatment with kahweol and melatonin induced PUMA up-regulation through endoplasmic reticulum stress-mediated C/EBP homologous protein induction and the p53-independent pathway. Our results collectively demonstrate that up-regulation of PUMA contributes to the sensitizing effect of melatonin plus kahweol on apoptosis in cancer cells.
褪黑素除了对昼夜节律有影响外，最近还被认为是调节生物过程的一种物质。然而，褪黑素调节细胞凋亡程序的机制仍知之甚少。在这项研究中，我们研究了褪黑素和卡瓦胡椒醇联合作用对癌细胞凋亡的影响，但对大多数正常人类细胞类型没有影响，因此为癌症治疗提供了一种有吸引力的新策略。在我们的实验中，褪黑素和卡瓦胡椒醇联合处理诱导细胞凋亡，刺激 DEVDase 活性和 DNA 片段化。用小干扰 RNA 下调 PUMA 的表达会减弱褪黑素和卡瓦胡椒醇诱导的细胞凋亡，而联合处理褪黑素和卡瓦胡椒醇则会通过内质网应激介导的 C/EBP 同源蛋白诱导和 p53 非依赖性途径上调 PUMA 的表达。我们的结果表明，上调 PUMA 有助于增强褪黑素和卡瓦胡椒醇对癌细胞凋亡的敏化作用。
