Sorafenib kills liver cancer cells by disrupting SCD1‐mediated synthesis of monounsaturated fatty acidsviathe ATP‐AMPK‐mTOR‐SREBP1 signaling pathway

Abstract

Sorafenib 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. FASEB J. 33,10089‐10103 (2019). http://www.fasebj.org

Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells

“…Inhibition of these targets, such as VEGFR and PDGFR, largely contributes to its clinical efficacy [65]. In recent years, other novel molecular targets of sorafenib have been discovered [16][17][18][19]. We previously mined the Connectivity Map (CMap) database to explore the potential molecular target(s) of sorafenib and found that sorafenib indirectly inhibited HDAC activity in HCC cells [66].…”

“…Downregulation of the components of cell survival pathways, such as myeloid cell leukemia-1 (MCL-1), and upregulation of pro-apoptotic Bcl-2 family proteins, such as p53 upregulated modulator of apoptosis (PUMA) and Bcl-2-interacting mediator of cell death (BIM), are associated with the apoptosis-inducing effects of sorafenib in HCC [14,15]. Recently, several novel anticancer targets of sorafenib have been identified, such as 5-hydroxytryptamine (5-HT) receptor [16], stearoyl coenzyme A desaturase 1 (SCD1) [17], and protein biosynthesis [18]. Especially, sorafenib is identified as a system x c − (a cell-surface Na + -independent cystine-glutamate antiporter) inhibitor that leads to endoplasmic reticulum (ER) stress and ferroptosis (an iron-dependent form of non-apoptotic programmed cell death) [19].…”

Citrus Peel Extract Ameliorates High-Fat Diet-Induced NAFLD via Activation of AMPK Signaling

“…The expressions of SREBP-1 and FAS were enhanced in the palmitate treatment than the control, but those were significantly decreased under the CPEW, CPEF or hesperidin. The CPEW, CPEF and hesperidin treatment also increased p-AMPK/AMPK ( Figure 9E), a main controlling upstream signaling on mTORC1 and ER stress and its associated hepatic lipogenesis genes [17]. Supplementation with CPEW, CPEF, and hesperidin reversed the elevations of mRNA factors involved in fatty acid synthesis.…”

“…Consistent with previous findings that the knockout of TSC1 or TSC2 induces UPR, resulting in mTOR-associated feedback inhibition of insulin action [22], it is noted that nutrient overload induces ER stress response in an mTORC1-dependent manner. In addition, chronic liver ER stress was observed in the steatosis of mice strains with genetically deficient in leptin as well as genetically modified IRE1/XBP1, PERK/eIF2α and ATF6 signaling pathways [17,20]. The ER stress response is one of the main features of pathological conditions associated with obesity and NAFLD [23][24][25].…”

Cytotoxic Thiodiketopiperazine Derivatives from the Deep Sea-Derived Fungus Epicoccum nigrum SD-388

“…All tests were performed in triplicate. The values of relative cell viability were calculated as percentages of absorbance from the treated samples to absorbance from the vehicle control [21].…”