{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:56:28Z","timestamp":1790891788415,"version":"4.1.0"},"reference-count":71,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Far Eastern Memorial Hospital-National Yang-Ming University Joint Research Program","award":["108DN19"],"award-info":[{"award-number":["108DN19"]}]},{"name":"Far Eastern Memorial Hospital-National Yang-Ming University Joint Research Program","award":["110DN19"],"award-info":[{"award-number":["110DN19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms23126501","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T10:25:12Z","timestamp":1654856712000},"page":"6501","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Orlistat Resensitizes Sorafenib-Resistance in Hepatocellular Carcinoma Cells through Modulating Metabolism"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2051-364X","authenticated-orcid":false,"given":"Pei-Wei","family":"Shueng","sequence":"first","affiliation":[{"name":"Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan"},{"name":"Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Wen","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei City 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3931-2127","authenticated-orcid":false,"given":"Wei-Chan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Radiology, Cathay General Hospital, Taipei City 106, Taiwan"},{"name":"School of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deng-Yu","family":"Kuo","sequence":"additional","affiliation":[{"name":"Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Yen","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei City 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1007\/s12029-017-9959-0","article-title":"Global Epidemiology of Hepatocellular Carcinoma (HCC Epidemiology)","volume":"48","author":"Ozakyol","year":"2017","journal-title":"J. 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