title: Activated δ‑opioid receptors inhibit hydrogen peroxide‑induced apoptosis in liver cancer cells through the PKC/ERK signaling pathway.
abstract: 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.
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Jia
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Deguang
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Sunbin
authors.initials: S
authors.lastname: Ling
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Sui
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D017465:Receptors, Opioid, delta; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases