Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu, Korea.
J Pineal Res. 2010 Oct;49(3):283-90. doi: 10.1111/j.1600-079X.2010.00793.x. Epub 2010 Jul 7.
Melatonin is an indolamine initially found to be produced in the pineal gland but now known to be synthesized in a variety of other tissues as well. The mechanisms whereby melatonin regulates the apoptotic program remain only partially understood. Anti-/pro-apoptotic effects of exogenous melatonin on various stimuli-mediated apoptosis were investigated in this report. We investigated the combined effect of melatonin and death receptor-mediated ligands (TNF-α, TRAIL, and anti-Fas antibody) or endoplasmic reticulum (ER) stress-inducing agents (thapsigargin, brefeldin A, and tunicamycin) on apoptosis of cancer cells. Death receptor- or ER stress-induced apoptosis was not significantly influenced by melatonin treatment. However, pretreatment with melatonin significantly inhibited DNA damage-induced apoptosis and glutathione (GSH) depletion, suggesting the reactive oxygen species mediate oxaliplatin/etoposide-induced apoptosis. Interestingly, we also found the involvement of myeloid cell leukemia-1 (Mcl-1) downregulation in oxaliplatin-induced apoptosis; thus, pretreatment with melatonin inhibited Mcl-1 downregulation, and ectopic expression of Mcl-1 attenuated oxaliplatin-induced apoptosis. Taken together, the results demonstrate that melatonin attenuates oxaliplatin-induced apoptosis in cancer cells by inhibition of GSH depletion and Mcl-1 downregulation.
褪黑素是一种吲哚胺，最初发现它在松果体中产生，但现在已知它也在许多其他组织中合成。褪黑素调节细胞凋亡程序的机制仍部分未知。本报告研究了外源性褪黑素对各种刺激介导的细胞凋亡的抗/促凋亡作用。我们研究了褪黑素与死亡受体介导的配体（TNF-α、TRAIL 和抗 Fas 抗体）或内质网（ER）应激诱导剂（他普西龙、布雷菲德菌素 A 和衣霉素）联合对癌细胞凋亡的影响。死亡受体或 ER 应激诱导的凋亡不受褪黑素处理的显著影响。然而，褪黑素预处理显著抑制了 DNA 损伤诱导的细胞凋亡和谷胱甘肽（GSH）耗竭，提示活性氧介导奥沙利铂/依托泊苷诱导的细胞凋亡。有趣的是，我们还发现髓样细胞白血病-1（Mcl-1）下调参与了奥沙利铂诱导的细胞凋亡；因此，褪黑素预处理抑制了 Mcl-1 的下调，而过表达 Mcl-1 则减弱了奥沙利铂诱导的细胞凋亡。总之，这些结果表明，褪黑素通过抑制 GSH 耗竭和 Mcl-1 下调来减轻奥沙利铂诱导的癌细胞凋亡。
