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Fatty Acid Synthase (FASN) Inhibitors Suppress Metformin-Induced Fat Accumulation and Apoptosis in H4IIE
1Department of Histology, Jeju National University College of Medicine, Jeju 63243, Korea.
Abstract:
We previously reported that metformin, a widely prescribed antidiabetic drug, induces the accumulation of triglyceride (TG) together with the apoptotic death of H4IIE via AMP-activated protein kinase (AMPK) in hepatocellular carcinoma (HCC) cells. However, the effect of cytoplasmic fat accumulation on the growth of HCCs remains controversial. Herein, we investigated the effect of fatty acid synthase (FASN) inhibitors on the basal- or metformin-induced changes including the content of cytoplasmic TG and the viability of HCC cells. Cerulenin and C75, inhibitors of FASN, did not significantly affect the basal TG content but dose-dependently suppressed the metformin-induced increase in the cytoplasmic TG content. Metformin-induced apoptosis of H4IIE cells was also significantly reduced by cerulenin and C75. Metformin enhanced the generation of reactive oxygen species which was suppressed by adding cerulenin or T75. Cerulenin also stimulated cell migration, which was suppressed by metformin. However, the degree of suppressive effect of metformin on TG synthesis, apoptosis, and cell migration was much more prominent by the inhibition of AMPK by compound C than cerulenin. In conclusion, our study found that excess fat accumulation is responsible for the apoptosis of H4IIE HCC cells and is informative for designing anti-tumor reagents, especially in HCC.
Insights
Metformin-induced fat accumulation causes hepatocellular carcinoma (HCC) cell death. Fatty acid synthase (FASN) inhibitors reduce this effect, suggesting fat accumulation drives HCC apoptosis.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Metformin, an antidiabetic drug, induces triglyceride accumulation and apoptosis in hepatocellular carcinoma (HCC) cells via AMP-activated protein kinase (AMPK).
- The role of cytoplasmic fat accumulation in HCC growth is debated.
- Fatty acid synthase (FASN) is a key enzyme in fatty acid synthesis.
Purpose of the Study:
- To investigate the impact of FASN inhibitors on metformin-induced changes in HCC cells.
- To determine the role of cytoplasmic triglyceride (TG) content and cell viability.
- To explore the relationship between FASN inhibition, metformin, and HCC progression.
Main Methods:
- Hepatocellular carcinoma (HCC) cell lines (H4IIE) were treated with metformin and FASN inhibitors (cerulenin, C75).
- Measurements included cytoplasmic triglyceride (TG) content, cell viability, reactive oxygen species (ROS) generation, and cell migration.
- AMP-activated protein kinase (AMPK) was inhibited using compound C for comparison.
Main Results:
- FASN inhibitors cerulenin and C75 suppressed metformin-induced increases in cytoplasmic TG content and H4IIE cell apoptosis.
- Metformin-enhanced reactive oxygen species (ROS) generation was reduced by cerulenin and C75.
- Metformin's suppressive effects on TG synthesis, apoptosis, and migration were less pronounced than AMPK inhibition.
Conclusions:
- Excessive fat accumulation mediates apoptosis in H4IIE HCC cells.
- FASN inhibitors can mitigate metformin-induced HCC cell death.
- Findings offer insights for developing novel anti-HCC therapeutic strategies targeting fat metabolism.
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