title: Diacylglycerol Metabolism and Signaling Is a Driving Force Underlying FASN Inhibitor Sensitivity in Cancer Cells.
abstract: Fatty acid synthase (FASN) generates the de novo source of lipids for cell proliferation and is a promising cancer therapy target. Development of FASN inhibitors, however, necessitates a better understanding of sensitive and resistant cancer types to optimize patient treatment. Indeed, testing the cytotoxic effects of FASN inhibition across human cancer cells revealed diverse sensitivities. We show here that metabolic incorporation of glucose into specific complex lipid species strongly predicts FASN inhibitor sensitivity. We also show that the levels of one of these lipid classes, protein kinase C (PKC) stimulator diacylglycerols, are lowered upon FASN inhibitor treatment in sensitive compared to resistant cells and that PKC activators and inhibitors rescue cell death in sensitive cells and sensitize resistant cells, respectively. Our findings not only reveal a biomarker for predicting FASN sensitivity in cancer cells but also a put forth a heretofore unrecognized mechanism underlying the anticancer effects of FASN inhibitors.
authors: †Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States.
authors: Daniel I
authors: DI
authors: Benjamin
authors: †Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States.
authors: Daniel S
authors: DS
authors: Li
authors: †Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States.
authors: Wallace
authors: W
authors: Lowe
authors: ‡3V Biosciences, Inc., 1050 Hamilton Ct., Menlo Park, California 94025, United States.
authors: Timothy
authors: T
authors: Heuer
authors: ‡3V Biosciences, Inc., 1050 Hamilton Ct., Menlo Park, California 94025, United States.
authors: George
authors: G
authors: Kemble
authors: †Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States.
authors: Daniel K
authors: DK
authors: Nomura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004075:Diglycerides / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004075:Diglycerides; D004791:Enzyme Inhibitors; D064429:Fatty Acid Synthases; D011493:Protein Kinase C; D005947:Glucose