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Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway
Liu, Ge1,2,3; Kuang, Shan1,2,3; Cao, Ruobing1,2,3; Wang, Ju1,2,3; Peng, Quancai1; Sun, Chaomin1,2,3
2019-09-01
Source PublicationFASEB JOURNAL
ISSN0892-6638
Volume33Issue:9Pages:10089-10103
Corresponding AuthorSun, Chaomin(sunchaomin@qdio.ac.cn)
AbstractSorafenib is a multikinase inhibitor that is effective in treating advanced liver cancer. Although its mechanism of action through several established cancer-related protein kinase targets is well-characterized, sorafenib induces variable responses among human tumors, and the cause for this variation is yet unknown. To investigate the underlying mechanisms, we applied mass spectrometry-based proteomic analysis to Huh7.5 human liver cancer cells and found that sorafenib significantly affected the expression of the key lipogenic enzymes, especially stearoyl coenzyme A desaturase 1 (SCD1), in these cells. Given that SCD1 catalyzes the most crucial and rate-limiting step in the synthesis of monounsaturated fatty acids (FAs), we performed a lipidomic analysis, which showed a dramatically altered lipid profile in sorafenib-treated cells. Detection and analysis of free FAs showed that the levels of monounsaturated FAs, including oleate, were significantly decreased in those cells treated by sorafenib. Addition of oleate protected liver cancer cells from sorafenib-induced death and alleviated the abnormalities of mitochondrial morphology and function caused by the drug. Treatment with sorafenib suppressed ATP production, resulting in AMPK activation via phosphorylation. Further secondary effects included reduction of the levels of sterol regulatory element-binding protein 1 (SREBP1) and the phosphorylation of mammalian target of rapamycin (mTOR) in liver cancer cells. These effects were partly abolished in the presence of compound C (an AMPK inhibitor) and ATP and adenosine, and SREBP1c overexpression also could be resistant to the effects of sorafenib, suggesting that the sorafenib-induced reduction in cell viability was mediated by the ATP-AMPK-mTOR-SREBP1 signaling pathway. Taken together, our results suggest that sorafenib's anticancer activity in liver cancer cells is based on the inhibition of ATP production, SCD1 expression, and monounsaturated FA synthesis. In addition, the decreased monounsaturated FA synthesis further triggered the more serious reduction of ATP production in sorafenib-treated cells. To our knowledge, this is the first evidence that sorafenib disrupts lipogenesis and triggers liver cancer cell death by targeting SCD1 through the ATP-AMPK-mTOR-SREBP1 pathway.-Liu, G., Kuang, S., Cao, R., Wang, J., Peng, Q., Sun, C. Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR- SREBP1 signaling pathway.
Keywordstearoyl CoA desaturase 1 monounsaturated FAs ATP production
DOI10.1096/fj.201802619RR
Indexed BySCI
Language英语
Funding ProjectChina Ocean Mineral Resources RD Association[DY135-B2-14] ; National Key R and D Program of China[2018YFC0310800] ; Natural Science Outstanding Youth Fund of Shandong Province[JQ201607] ; National Natural Science Foundation of China[31470181] ; Taishan Young Scholar Program of Shandong Province[tsqn20161051] ; AoShan Talents Program - Qingdao National Laboratory for Marine Science and Technology[2015ASTP] ; 100-Talent Project of the Chinese Academy of Sciences
WOS Research AreaBiochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics ; Cell Biology
WOS SubjectBiochemistry & Molecular Biology ; Biology ; Cell Biology
WOS IDWOS:000482214200030
PublisherFEDERATION AMER SOC EXP BIOL
Citation statistics
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/162373
Collection实验海洋生物学重点实验室
Corresponding AuthorSun, Chaomin
Affiliation1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao, Shandong, Peoples R China
2.Chinese Acad Sci, Ctr Ocean Mega Sci, Qingdao, Shandong, Peoples R China
3.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao, Shandong, Peoples R China
First Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Corresponding Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
Liu, Ge,Kuang, Shan,Cao, Ruobing,et al. Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway[J]. FASEB JOURNAL,2019,33(9):10089-10103.
APA Liu, Ge,Kuang, Shan,Cao, Ruobing,Wang, Ju,Peng, Quancai,&Sun, Chaomin.(2019).Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway.FASEB JOURNAL,33(9),10089-10103.
MLA Liu, Ge,et al."Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway".FASEB JOURNAL 33.9(2019):10089-10103.
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