Melatonin reverses tunicamycin-induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing CHOP and decreasing Survivin
Melatonin reverses tunicamycin-induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing CHOP and decreasing Survivin
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褪黑激素逆转衣霉素诱导的人肝细胞癌细胞内质网应激，并通过增加 CHOP 和减少 Survivin 改善对多柔比星的细胞毒性反应
DOI：
10.1111/jpi.12061
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发表时间：
2013-09-01
影响因子：
10.3
通讯作者：
Wei, Wei
中科院分区：
文献类型：
--
作者：
Fan, Lulu;Sun, Guoping;Wei, Wei
肝细胞癌（HCC）的化疗耐药性与多种细胞对环境应激（如营养剥夺和缺氧）的反应有关。然而，营养缺乏和肿瘤缺氧引起的内质网应激是否有助于耐药仍不清楚。在我们以前的研究中，褪黑激素增加了肝细胞癌化疗药物的疗效。然而，褪黑激素对内质网（ER）应激诱导的肝癌化疗药物耐药性的影响尚未得到证实。本研究探讨了内质网（ER）应激反应在人肝癌细胞对阿霉素耐药过程中的作用。用内质网应激诱导剂衣霉素预处理HepG 2和SMMC-7721细胞（两种人肝癌细胞系），可显著降低阿霉素诱导的细胞凋亡率。有趣的是，衣霉素和褪黑激素共同预处理显着增加阿霉素诱导的细胞凋亡。同时，在给予衣霉素的HepG 2和SMMC-7721细胞中磷酸化AKT（p-AKT）的表达升高，但在褪黑素存在下降低。此外，与通过使用PI 3 K抑制剂LY 294002抑制AKT活化一致，褪黑激素升高CHOP（C/EBP同源蛋白）的水平并降低Survivin（凋亡蛋白家族抑制剂的成员）的水平，表明褪黑激素逆转ER应激诱导的人肝细胞癌细胞中对阿霉素的抗性。这些结果表明褪黑激素通过下调PI 3 K/AKT通路、增加CHOP水平和降低Survivin水平来减弱ER应激诱导的人肝癌细胞对阿霉素的抗性。
Chemoresistance in hepatocellular carcinoma (HCC) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whether ER stress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (ER) stress-induced resistance to chemotherapeutic agents in HCC have not been tested. The effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 and SMMC-7721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, an ER stress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co-pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylated AKT (p-AKT) was elevated in HepG2 and SMMC-7721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition of AKT activation by using the PI3K inhibitor LY294002, melatonin elevated the levels of CHOP (C/EBP-homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family) suggesting that inhibition of the PI3K/AKT pathway by melatonin-reversed ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuates ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by down-regulating the PI3K/AKT pathway, increasing the levels of CHOP and decreasing the levels of Survivin.