Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells

  1. Get@NRC: Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells (Opens in a new window)
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Journal titleExperimental Biology and Medicine
Pages10071017; # of pages: 11
Subjectacyl coenzyme A desaturase 1; acyl coenzyme A desaturase inhibitor; cvt 11127; enzyme inhibitor; epidermal growth factor receptor; gefitinib; mammalian target of rapamycin; mitogen activated protein kinase; monounsaturated fatty acid; protein kinase B; saturated fatty acid; unclassified drug; article; cancer cell; cell membrane; cell metabolism; cell proliferation; cell survival; controlled study; cytotoxicity; drug effect; drug potentiation; drug sensitivity; enzyme activity; enzyme inhibition; human; human cell; lipid blood level; lung cancer; microenvironment; mitogenesis; protein phosphorylation; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Extracellular Signal-Regulated MAP Kinases; Humans; Lung Neoplasms; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Quinazolines; Receptor, Epidermal Growth Factor; Stearoyl-CoA Desaturase; TOR Serine-Threonine Kinases; Mammalia
AbstractStearoyl-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 signalregulated 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. © 2008 Society for Experimental Biology and Medicine.
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AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Nutrisciences and Health (INH-ISNS)
Peer reviewedYes
NPARC number21269526
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Record identifier0f6064d7-67c2-43f0-91c6-ffdcab23ffe5
Record created2013-12-12
Record modified2016-05-09
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