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

Abstract

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 MSeAinduced death. In our current research, we found that the addition of PA increased the sensitivity of HepG2 cells to low-dose MSeAinduced 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.

GPRC6A is a key mediator of palmitic acid regulation of lipid synthesis in bovine mammary epithelial cells

“…These data elucidate that, at low concentrations, PA is a key stimulator on cellular signaling pathways leading to lipid synthesis, whereas at higher concentrations, PA inhibits these signaling pathways and might have cytotoxic effects. Previous reports show that an overload of PA has a lipotoxicity impact on cell function and induces cell apoptosis (Chu et al, 2019; Deng et al, 2020; H. Zhang et al, 2021). It is worth studying in the future the dose‐dependent effect of PA on apoptosis of BMECs.…”

Palmitic Acid Inhibits Cell Proliferation and Tumor Growth of Endometrial Cancer In Vitro and In Vivo

“…In addition to cellular stress, PA-mediated apoptosis appears to involve a number of relevant factors and signaling pathways including p53, p62, p21, Sesn2, CD36, S6K1 and the PI3K/Akt pathway (64)(65)(66)(67). PA can exert apoptotic effects through mitochondrial apoptotic pathways, including upregulation of CCAAT-enhancer-binding protein homologous proteins (CHOP) (68). p53 negatively regulated PA-induced apoptosis by ROS accumulation via targeting downstream genes including p21 and Sesn2 in HCT116 cells (55).…”

Secondary Metabolites with Biomedical Applications from Plants of the Sarraceniaceae Family

“…Cytotoxic effects of palmitic acid alone or in combination with other fatty acids have also been observed in breast cancer cells [ 252 ], hepatocyte carcinoma cells [ 253 ] and colon carcinoma cells [ 254 , 255 ].…”