Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis
Abstract Background Sorafenib resistance is a key impediment to successful treatment of patients with advanced hepatocellular carcinoma (HCC) and recent studies have reported reversal of drug resistance by targeting ferroptosis. The present study aimed to explore the association of fatty acid syntha...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Online Access: | https://doi.org/10.1186/s13046-022-02567-z |
| _version_ | 1797958393379422208 |
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| author | Yan Li Wenjuan Yang Yuanyuan Zheng Weiqi Dai Jie Ji Liwei Wu Ziqi Cheng Jie Zhang Jingjing Li Xuanfu Xu Jianye Wu Mingwei Yang Jiao Feng Chuanyong Guo |
| author_facet | Yan Li Wenjuan Yang Yuanyuan Zheng Weiqi Dai Jie Ji Liwei Wu Ziqi Cheng Jie Zhang Jingjing Li Xuanfu Xu Jianye Wu Mingwei Yang Jiao Feng Chuanyong Guo |
| author_sort | Yan Li |
| collection | DOAJ |
| description | Abstract Background Sorafenib resistance is a key impediment to successful treatment of patients with advanced hepatocellular carcinoma (HCC) and recent studies have reported reversal of drug resistance by targeting ferroptosis. The present study aimed to explore the association of fatty acid synthase (FASN) with sorafenib resistance via regulation of ferroptosis and provide a novel treatment strategy to overcome the sorafenib resistance of HCC patients. Methods Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Biological information analyses, immunofluorescence assays, western blot assays, and co-immunoprecipitation analyses were conducted to elucidate the functions of FASN in HCC. Both in vitro and in vivo studies were conducted to examine the antitumor effects of the combination of orlistat and sorafenib and CalcuSyn software was used to calculate the combination index. Results Solute carrier family 7 member 11 (SLC7A11) was found to play an important role in mediating sorafenib resistance. The up-regulation of FASN antagonize of SLC7A11-mediated ferroptosis and thereby promoted sorafenib resistance. Mechanistically, FASN enhanced sorafenib-induced ferroptosis resistance by binding to hypoxia-inducible factor 1-alpha (HIF1α), promoting HIF1α nuclear translocation, inhibiting ubiquitination and proteasomal degradation of HIF1α, and subsequently enhancing transcription of SLC7A11. Orlistat, an inhibitor of FASN, with sorafenib had significant synergistic antitumor effects and reversed sorafenib resistance both in vitro and in vivo. Conclusion Targeting the FASN/HIF1α/SLC7A11 pathway resensitized HCC cells to sorafenib. The combination of orlistat and sorafenib had superior synergistic antitumor effects in sorafenib-resistant HCC cells. |
| first_indexed | 2024-04-11T00:19:21Z |
| format | Article |
| id | doaj.art-1d317e57a4e94150b8a72d58c3a8d94c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-11T00:19:21Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-1d317e57a4e94150b8a72d58c3a8d94c2023-01-08T12:23:36ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-01-0142111910.1186/s13046-022-02567-zTargeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosisYan Li0Wenjuan Yang1Yuanyuan Zheng2Weiqi Dai3Jie Ji4Liwei Wu5Ziqi Cheng6Jie Zhang7Jingjing Li8Xuanfu Xu9Jianye Wu10Mingwei Yang11Jiao Feng12Chuanyong Guo13Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Emergency, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shidong HospitalDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shidong HospitalDepartment of Gastroenterology, Shidong HospitalDepartment of Gastroenterology, Putuo People’s Hospital, Tongji UniversityDepartment of Oncology Radiotherapy, The First Affiliated Hospital of Anhui Medical UniversityDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineAbstract Background Sorafenib resistance is a key impediment to successful treatment of patients with advanced hepatocellular carcinoma (HCC) and recent studies have reported reversal of drug resistance by targeting ferroptosis. The present study aimed to explore the association of fatty acid synthase (FASN) with sorafenib resistance via regulation of ferroptosis and provide a novel treatment strategy to overcome the sorafenib resistance of HCC patients. Methods Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Biological information analyses, immunofluorescence assays, western blot assays, and co-immunoprecipitation analyses were conducted to elucidate the functions of FASN in HCC. Both in vitro and in vivo studies were conducted to examine the antitumor effects of the combination of orlistat and sorafenib and CalcuSyn software was used to calculate the combination index. Results Solute carrier family 7 member 11 (SLC7A11) was found to play an important role in mediating sorafenib resistance. The up-regulation of FASN antagonize of SLC7A11-mediated ferroptosis and thereby promoted sorafenib resistance. Mechanistically, FASN enhanced sorafenib-induced ferroptosis resistance by binding to hypoxia-inducible factor 1-alpha (HIF1α), promoting HIF1α nuclear translocation, inhibiting ubiquitination and proteasomal degradation of HIF1α, and subsequently enhancing transcription of SLC7A11. Orlistat, an inhibitor of FASN, with sorafenib had significant synergistic antitumor effects and reversed sorafenib resistance both in vitro and in vivo. Conclusion Targeting the FASN/HIF1α/SLC7A11 pathway resensitized HCC cells to sorafenib. The combination of orlistat and sorafenib had superior synergistic antitumor effects in sorafenib-resistant HCC cells.https://doi.org/10.1186/s13046-022-02567-z |
| spellingShingle | Yan Li Wenjuan Yang Yuanyuan Zheng Weiqi Dai Jie Ji Liwei Wu Ziqi Cheng Jie Zhang Jingjing Li Xuanfu Xu Jianye Wu Mingwei Yang Jiao Feng Chuanyong Guo Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis Journal of Experimental & Clinical Cancer Research |
| title | Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis |
| title_full | Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis |
| title_fullStr | Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis |
| title_full_unstemmed | Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis |
| title_short | Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis |
| title_sort | targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis |
| url | https://doi.org/10.1186/s13046-022-02567-z |
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