Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress-induced apoptosis
Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress-induced apoptosis
复制标题
褪黑素使人肝癌细胞对内质网应激诱导的细胞凋亡敏感
DOI：
10.1111/j.1600-079x.2011.00946.x
复制
发表时间：
2012-04-01
影响因子：
10.3
通讯作者：
Wei, Wei
中科院分区：
文献类型：
--
作者：
Zha, Lixia;Fan, Lulu;Wei, Wei
内质网应激介导的细胞凋亡与癌症的发展有关。褪黑激素诱导肝癌细胞凋亡的实验研究，但褪黑激素对内质网（ER）应激诱导的肝癌细胞凋亡的影响还没有被测试。用衣霉素（ER应激诱导剂）处理人肝癌细胞和正常人肝细胞，研究ER应激诱导细胞凋亡的差异。HepG 2细胞（肝癌细胞）和HL-7702细胞（正常人肝细胞）之间的凋亡率观察到显著差异。HepG 2细胞中环氧合酶2（考克斯2）的表达增加，而HL 7702细胞中COX 2的表达无明显变化。此外，使用考克斯-2抑制剂塞来昔布下调考克斯-2表达，增加衣霉素诱导的凋亡，同时上调促凋亡转录因子CHOP（GADD 153）和下调B细胞淋巴瘤2/Bcl-2相关X蛋白（Bcl-2/Bax）比值，表明抑制考克斯-2使人肝癌细胞对ER应激诱导的凋亡敏感。有趣的是，衣霉素和褪黑素联合处理也降低了考克斯-2的表达，并通过升高CHOP水平和降低Bcl-2/Bax比值来显著增加凋亡率。这些结果表明，褪黑素通过下调考克斯-2表达，增加CHOP水平和降低Bcl-2/Bax比值，使人肝癌细胞对ER应激诱导的凋亡敏感。
Endoplasmic reticulum stressmediated 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) stressinduced apoptosis in HCC have not been tested. Differences in ER stressinduced 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-2associated X protein (Bcl-2/Bax) ratio, suggesting that inhibition of COX-2 sensitized human hepatoma cells to ER stressinduced 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 stressinduced apoptosis by down-regulating COX-2 expression, increasing the levels of CHOP and decreasing the Bcl-2/Bax ratio.