Orlistat Resensitizes Sorafenib-Resistance in Hepatocellular Carcinoma Cells through Modulating Metabolism
Pei-Wei Shueng1,2, Hui-Wen Chan3, Wei-Chan Lin4,5
1Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan.
Abstract:
Sorafenib is one of the options for advanced hepatocellular carcinoma treatment and has been shown to extend median overall survival. However, sorafenib resistance often develops a few months after treatment. Hence, developing various strategies to overcome sorafenib resistance and understand the possible mechanisms is urgently needed. We first established sorafenib-resistant hepatocellular carcinoma (HCC) cells. Then, we found that sorafenib-resistant Huh7 cells (Huh7/SR) exhibit higher glucose uptakes and express elevated fatty acid synthesis and glucose metabolism-related proteins than their parental counterparts (Huh7). The current study investigated whether sorafenib resistance could be reversed by suppressing fatty acid synthesis, using a fatty acid synthase (FASN) inhibitor, orlistat, in HCC cells. FASN inhibition-caused changes in protein expressions and cell cycle distribution were analyzed by Western blot and flow cytometry, and changes in glucose uptakes were also evaluated by 18F-FDG uptake. Orlistat remarkably enhanced the cytotoxicity of sorafenib in both Huh7 and Huh7/SR cells, and flow cytometry showed that combination treatment significantly increased the sub-G1 population in both cell lines. Western blot revealed that the combination treatment effectively increased the ratio of Bax/Bcl-2 and decreased expressions of pERK; additionally, the combination treatment also strongly suppressed fatty acid synthesis-related proteins (e.g., FASN and SCD) in both cell lines. Lastly, the 18F-FDG uptake was repressed by the combination treatment in both cell lines. Our results indicated that orlistat-mediated FASN inhibition could overcome sorafenib resistance and enhance cell killing in HCC by changing cell metabolism.
Insights
Sorafenib resistance in liver cancer can be overcome by inhibiting fatty acid synthase (FASN) with orlistat. This combination therapy enhances sorafenib
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Cancer metabolism and drug resistance
- Pharmacology and targeted therapy
Background:
- Sorafenib extends survival in advanced liver cancer but resistance develops quickly.
- Sorafenib-resistant HCC cells show increased glucose uptake and altered metabolism.
- Understanding resistance mechanisms is crucial for developing new treatment strategies.
Purpose of the Study:
- To investigate if inhibiting fatty acid synthesis can reverse sorafenib resistance in HCC.
- To evaluate the efficacy of combining a fatty acid synthase (FASN) inhibitor, orlistat, with sorafenib.
Main Methods:
- Established sorafenib-resistant HCC cell lines (Huh7/SR).
- Utilized Western blot, flow cytometry, and 18F-FDG uptake assays.
- Assessed changes in protein expression, cell cycle, glucose uptake, and fatty acid synthesis.
Main Results:
- Orlistat enhanced sorafenib's cytotoxicity and increased apoptosis (sub-G1 population).
- Combination treatment modulated apoptosis-related proteins (Bax/Bcl-2 ratio) and suppressed pERK.
- Orlistat inhibited fatty acid synthesis proteins (FASN, SCD) and reduced glucose uptake in both cell lines.
Conclusions:
- Orlistat-mediated FASN inhibition effectively overcomes sorafenib resistance in HCC.
- Combination therapy enhances cancer cell killing by altering cellular metabolism.
- Targeting fatty acid synthesis presents a promising strategy to combat sorafenib resistance in liver cancer.
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