Jia Kaiqi, Sun Deguang, Ling Sunbin, Tian Yu, Yang Xuejun, Sui Jidong, Tang Bo, Wang Liming
Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
Department of Hepatobiliary Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China.
Mol Med Rep. 2014 Aug;10(2):839-47. doi: 10.3892/mmr.2014.2301. Epub 2014 Jun 5.
Apoptotic liver cancer cells have important roles in liver tumorigenesis and liver cancer progression. Recent studies have shown that δ‑opioid receptors are highly expressed in human liver and liver cancer cells. The present study aimed to investigate the role of activated δ‑opioid receptors on human liver cancer cell apoptosis and its interrelation with the mitochondria and the protein kinase C/extracellular‑signal‑regulated kinase (PKC/ERK) signaling pathway. H2O2 was used to induce apoptosis in human liver cancer cells. During apoptosis, mitochondrial transmembrane potentials were observed to decrease, cytochrome c expression was found to increase and B cell lymphoma 2 (Bcl‑2) expression decreased. These findings suggested that H2O2‑induced apoptosis was mediated through the mitochondrial pathway. Of note, activated δ‑opioid receptors were observed to inhibit H2O2‑induced apoptosis in human liver cancer cells. Following δ‑opioid receptor activation, the number of apoptotic liver cancer cells decreased, mitochondrial transmembrane potentials were restored, cytoplasmic cytochrome c and Bcl‑2‑associated X protein expression decreased and Bcl‑2 expression increased. These data suggested that δ‑opioid receptor activation inhibited mitochondria‑mediated apoptosis. In addition, activation of δ‑opioid receptors was observed to increase the expression of PKC and ERK in human liver cancer cells. Furthermore, upon inhibition of the PKC/ERK signaling pathway, the protective effect associated with the δ‑opioid receptor on liver cancer cell apoptosis was inhibited, which was not associated with the status of δ‑opioid receptor activation. These findings suggested that the PKC/ERK signaling pathway has an important role in δ‑opioid receptor‑mediated inhibition of apoptosis in human liver cancer cells.
凋亡的肝癌细胞在肝脏肿瘤发生和肝癌进展中发挥着重要作用。最近的研究表明，δ-阿片受体在人肝脏和肝癌细胞中高度表达。本研究旨在探讨激活的δ-阿片受体对人肝癌细胞凋亡的作用及其与线粒体和蛋白激酶C/细胞外信号调节激酶（PKC/ERK）信号通路的相互关系。使用过氧化氢诱导人肝癌细胞凋亡。在凋亡过程中，观察到线粒体跨膜电位降低，细胞色素c表达增加，B细胞淋巴瘤2（Bcl-2）表达降低。这些发现表明，过氧化氢诱导的凋亡是通过线粒体途径介导的。值得注意的是，观察到激活的δ-阿片受体可抑制过氧化氢诱导的人肝癌细胞凋亡。δ-阿片受体激活后，凋亡的肝癌细胞数量减少，线粒体跨膜电位恢复，细胞质细胞色素c和Bcl-2相关X蛋白表达降低，Bcl-2表达增加。这些数据表明，δ-阿片受体激活抑制了线粒体介导的凋亡。此外，观察到δ-阿片受体激活可增加人肝癌细胞中PKC和ERK的表达。此外，抑制PKC/ERK信号通路后，与δ-阿片受体相关的对肝癌细胞凋亡的保护作用受到抑制，这与δ-阿片受体的激活状态无关。这些发现表明，PKC/ERK信号通路在δ-阿片受体介导的抑制人肝癌细胞凋亡中起重要作用。
