Role of Stearoyl-CoA desaturase-1 (SCD1) in the activation of epidermal growth factor receptor (EGFR) in lung cancer cells

Cancer cells activate lipogenic enzymes, including StearoylCoA Desaturase-1 (SCD1), the key enzyme that converts saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA). Previously, we established that SCD1 regulates lipogenesis, cell proliferation and invasiveness in lung cancer cells, as well as tumor formation in mice. We recently reported that SCD1 modulates the PI3K/Akt pathway, a central signaling cascade, along with ERK, which are involved in the regulation of lipid biosynthesis, growth and survival of mammalian cells. Growth factor-activated tyrosine kinase receptors, such as epidermal growth factor (EGF) receptors (EGFR), are main activators of Akt and ERK signals, two cascades that are most often deranged in cancer. A hallmark of cancer is the metabolic shift towards macromolecular synthesis to support cell replication. SCD1 expression increases in cancer cells. The molecular mechanisms by which SCD1 regulates the biological phenotype of cancer cells is still unknown. The poor prognosis and ineffective treatments of some cancers, such as lung cancer, calls for better understanding of their mechanisms and for finding novel targets that, like SCD1, modulate the Akt and ERK pathways. Here we provide evidence that SCD1 activity controls the activation of EGFR and its downstream signaling targets, Akt and ERK. Using H460 human lung cancer cells, we observed that the activating phosphorylation of Tyr1068 and Tyr1086 residues in EGFR upon EGF stimulation was markedly impaired when SCD1 activity was blocked with CVT-11127, a novel small molecule SCD inhibitor. In addition, supplementation with oleic acid, the product of SCD1, restored EGF-induced phosphorylation of EGFR but not the full phosphorylation of Akt. Finally, abrogation of SCD1 dramatically altered distribution of rafts and non-raft domains, suggesting that the regulation of EGFR function by SCD1 may involve the alteration of membrane lipid domains. All results are representative of 3 separate experiments. In conclusion, our data indicate that SCD1 may coordinate the regulation of lipid biosynthesis and the transduction signals that control cancer cell metabolism, proliferation, survival and tumorigenesis by modulating EGFR activation, which subsequently modifies the Akt and ERK signaling platforms. Our findings also suggest SCD1 is a potential target for novel pharmacological interventions in lung cancer.M.S.Includes bibliographical referencesby Mary Nashe