title: Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells.
abstract: Stearoyl-CoA desaturase-1 (SCD1), the main enzyme that converts saturated fatty acids into monounsaturated fatty acids, is a key factor in the mechanisms of cancer cell proliferation, survival and tumorigenesis. Evidence indicates that SCD1 activity regulates these events in part by targeting the phosphatidylinositol-3 phosphate kinase/Akt and Ras/extracellular signal-regulated kinase (ERK) pathways, but the molecular mechanisms remain unknown. We now show that in H460 lung cancer cells, the suppression of SCD activity with CVT-11127, a specific small molecule SCD inhibitor, impairs the ligand-induced phosphorylation of epidermal growth factor (EGF) receptor, causing the inactivation of its downstream targets Akt, ERK and mammalian target of rapamycin. Importantly, the mitogenic response to EGF was markedly defective in SCD-depleted cancer cells. The inactivation of EGF receptor (EGFR) promoted by SCD inhibition may be caused by perturbations in the lipid microenvironment surrounding the receptor, since we detected significant alterations in the lateral mobility of plasma lipid microdomains. Finally, incubation of lung cancer cells with SCD blockers potentiated the antigrowth effect of gefitinib, an EGFR inhibitor employed in cancer treatment. Altogether, our data indicate that SCD activity may control cancer cell metabolism, proliferation and survival by modulating the EGFR→Akt/ERK signaling platforms. Our studies also suggest a value for SCD inhibitors as novel pharmacological agents in lung cancer, one of the most common and lethal forms of cancer for which therapeutic options remain very limited.
authors.affiliation: Department of Nutritional Sciences and Rutgers Center for Lipid Research, Rutgers, State University of New Jersey, 96 Lipman Drive, New Brunswick, NJ 08901-8525, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Nashed
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Chisholm
authors.forename: R Ariel
authors.initials: RA
authors.lastname: Igal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D013230:Stearoyl-CoA Desaturase; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human