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The endoplasmic reticulum stress response is associated with insulin resistance-mediated drug resistance in HepG2
Unlabelled:
Insulin resistance has a close relationship with tumorigenesis, tumor progression, and cancer prognosis. Importantly, the liver is the main target tissue of insulin, and the resistance to chemotherapeutic agents has been reported in hepatocarcinoma. However, little is known about the relationship between drug resistance and insulin resistance in hepatocarcinoma. Therefore, we treated HepG2 cells (a human hepatoma cell line) with high concentrations of insulin to establish a cell-based model of insulin resistance (HepG2/IR cells) to define the relationship between insulin resistance and the resistance to chemotherapy. We identified that HepG2/IR cells exhibited stable insulin resistance, with decreased glucose consumption, reduced glycogen synthesis, and decreased expression of the insulin receptor gene. HepG2/IR cells also exhibited endoplasmic reticulum (ER) dilatation and degranulation. Molecular markers of endoplasmic reticulum stress, including glucose-regulated protein78 (GRP78) and phosphorylated protein kinase R-like ER kinase (p-PERK), increased significantly, which was accompanied by increased reactive oxygen metabolism and decreased mitochondrial membrane potential. In addition, HepG2/IR cells were resistant to the chemotherapy agent Adriamycin, which was accompanied by the upregulation of multidrug resistance gene 1/ P-glycoprotein (P-gp; an endoplasmic reticulum chaperone that plays a role in ER stress), and enhanced drug efflux. These data suggest that the endoplasmic reticulum (ER) stress response was active in HepG2/IR cells, and that insulin resistance was related to drug resistance in HepG2 cells. Interestingly, the ER stress and chemotherapy resistance observed in HepG2/IR cells could be reversed by treatment with the insulin sensitizer pioglitazone. Therefore, our study suggests that there is a close relationship between the resistance to chemotherapy and insulin resistance in HepG2 cells, and that the ER stress response play a role in insulin resistance-mediated drug resistance in hepatocarcinoma cells.
Keywords:
Insulin resistance, drug resistance, P-gp, endoplasmic reticulum stress, HepG2 cells.
Insights
Insulin resistance in hepatocarcinoma cells promotes chemotherapy resistance, linked to endoplasmic reticulum stress. This resistance can be reversed by insulin sensitizers like pioglitazone.
Area of Science:
- Hepatocellular carcinoma research
- Cancer biology
- Endocrinology
Background:
- Insulin resistance is linked to cancer development and progression.
- Hepatocellular carcinoma exhibits resistance to chemotherapy.
- The interplay between insulin resistance and drug resistance in hepatocarcinoma is not well understood.
Purpose of the Study:
- To investigate the relationship between insulin resistance and chemotherapy drug resistance in hepatocarcinoma cells.
- To establish a cell-based model for studying insulin resistance in hepatoma cells.
- To explore the role of endoplasmic reticulum stress in this context.
Main Methods:
- Established an insulin-resistant HepG2 cell line (HepG2/IR) by treating with high insulin concentrations.
- Assessed insulin resistance markers, including glucose consumption, glycogen synthesis, and insulin receptor gene expression.
- Analyzed endoplasmic reticulum (ER) morphology, ER stress markers (GRP78, p-PERK), reactive oxygen species, and mitochondrial membrane potential.
- Investigated Adriamycin resistance, multidrug resistance gene 1/P-glycoprotein (P-gp) expression, and drug efflux in HepG2/IR cells.
- Evaluated the effect of pioglitazone on ER stress and chemotherapy resistance.
Main Results:
- HepG2/IR cells demonstrated stable insulin resistance with altered metabolic markers and decreased insulin receptor expression.
- ER dilatation, degranulation, and increased ER stress markers (GRP78, p-PERK) were observed in HepG2/IR cells.
- Increased reactive oxygen metabolism and decreased mitochondrial membrane potential were noted.
- HepG2/IR cells exhibited resistance to Adriamycin, associated with P-gp upregulation and enhanced drug efflux.
- Pioglitazone treatment reversed ER stress and chemotherapy resistance in HepG2/IR cells.
Conclusions:
- Insulin resistance in HepG2 cells is closely associated with resistance to chemotherapy agents.
- Endoplasmic reticulum stress plays a significant role in mediating drug resistance in insulin-resistant hepatocarcinoma cells.
- Targeting ER stress or using insulin sensitizers may offer therapeutic strategies for overcoming chemotherapy resistance in hepatocarcinoma.
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