Combination of Palmitic Acid and Methylseleninic Acid Induces Mitochondria-Dependent Apoptosis via Attenuation of the IRE1α Arm and Enhancement of CHOP in Hepatoma

[Image: see text] The most common saturated fatty acid in the human diet is palmitic acid (PA), and emerging evidence suggests that it may have anticancer activity. Methylseleninic acid (MSeA), the most commonly used selenium derivative in humans, has specific cytotoxic effects on several cancer cells. However, it is generally considered that HepG2 cells are insensitive to MSeA-induced death. In our current research, we found that the addition of PA increased the sensitivity of HepG2 cells to low-dose MSeA-induced apoptosis. The anticancer efficacy of the MSeA/PA combination was also demonstrated in a HepG2 xenograft model. Further experiments revealed that IRE1 inhibition significantly enhanced the PA-induced apoptosis, indicating the prosurvival function of IRE1 in PA treatment of HepG2 cells. The combination of PA and MSeA attenuated the IRE1 pathway and increased the expressions of phospha-eIF2α and GADD153/C/EBP homologous protein (CHOP), contributing to the PA/MSeA combination-induced mitochondria-dependent apoptosis in HepG2 cells. In addition, PA downregulated the expression of the glucose transporter GLUT1 and restricted glucose metabolism, thus promoting the apoptosis of tumor cells. Considering the lipotoxicity of PA, L02 human normal hepatocytes were used to evaluate the effect of MSeA on the lipotoxicity caused by PA. Interestingly, MSeA prevented PA-induced lipotoxicity in L02 cells. Our findings provided evidence that PA may be a promising and excellent sensitizer for improving the anticancer effect of MSeA in hepatoma chemotherapy.