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.