Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
J Pineal Res. 2012 Apr;52(3):322-31. doi: 10.1111/j.1600-079X.2011.00946.x. Epub 2012 Jan 8.
Endoplasmic reticulum stress-mediated cell apoptosis is implicated in the development of cancer. Melatonin induces apoptosis in hepatocellular carcinoma (HCC) in experimental studies, but the effects of melatonin on endoplasmic reticulum (ER) stress-induced apoptosis in HCC have not been tested. Differences in ER stress-induced apoptosis in human hepatoma cells and normal human hepatocyte were investigated by exposure to tunicamycin (ER stress inducer). Significant differences were observed in the rate of apoptosis between HepG2 cells (hepatoma cells) and HL-7702 cells (normal human hepatocyte cells). The expression of cyclooxygenase-2 (COX-2) was increased in HepG2 cells but not in HL-7702 cells. Furthermore, down-regulation of COX-2 expression using the COX-2 inhibitor, celecoxib, increased tunicamycin-induced apoptosis concomitant with the up-regulation of pro-apoptotic transcription factor CHOP (GADD153) and down-regulation of B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio, suggesting that inhibition of COX-2 sensitized human hepatoma cells to ER stress-induced apoptosis. Interestingly, co-treatment with tunicamycin and melatonin also decreased the expression of COX-2 and significantly increased the rate of apoptosis by elevating the levels of CHOP and reducing the Bcl-2/Bax ratio. These results demonstrate that melatonin sensitizes human hepatoma cells to ER stress-induced apoptosis by down-regulating COX-2 expression, increasing the levels of CHOP and decreasing the Bcl-2/Bax ratio.
内质网应激介导的细胞凋亡与癌症的发展有关。褪黑素在实验研究中诱导肝癌（HCC）细胞凋亡，但褪黑素对 HCC 细胞内质网（ER）应激诱导的凋亡的影响尚未得到检验。通过用他莫昔芬（ER 应激诱导剂）处理人肝癌细胞和正常肝细胞，研究了 ER 应激诱导的凋亡的差异。在 HepG2 细胞（肝癌细胞）和 HL-7702 细胞（正常肝细胞）之间观察到凋亡率有显著差异。HepG2 细胞中环氧合酶-2（COX-2）的表达增加，但在 HL-7702 细胞中没有。此外，使用 COX-2 抑制剂塞来昔布下调 COX-2 的表达，增加了他莫昔芬诱导的凋亡，同时上调了促凋亡转录因子 CHOP（GADD153），下调了 B 细胞淋巴瘤 2/Bcl-2 相关 X 蛋白（Bcl-2/Bax）的比值，表明 COX-2 的抑制使肝癌细胞对 ER 应激诱导的凋亡敏感。有趣的是，他莫昔芬和褪黑素的联合治疗也降低了 COX-2 的表达，通过增加 CHOP 的水平和降低 Bcl-2/Bax 的比值，显著增加了凋亡率。这些结果表明，褪黑素通过下调 COX-2 的表达，增加 CHOP 的水平和降低 Bcl-2/Bax 的比值，使肝癌细胞对 ER 应激诱导的凋亡敏感。
