Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells
Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells
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DOI：
10.1258/ebm.2012.012126
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发表时间：
2012-09-01
影响因子：
3.2
通讯作者：
Igal, R. Ariel
中科院分区：
文献类型：
--
作者：
Nashed, Mary;Chisholm, Jeffrey W.;Igal, R. Ariel
硬脂酰辅酶A去饱和酶-1（SCD 1）是将饱和脂肪酸转化为单不饱和脂肪酸的主要酶，是癌细胞增殖、生存和肿瘤发生机制的关键因素。有证据表明，SCD 1活性调节这些事件的一部分，通过靶向磷脂酰肌醇-3磷酸激酶/Akt和Ras/细胞外信号调节激酶（ERK）途径，但分子机制仍然未知。我们现在表明，在H460肺癌细胞中，用CVT-11127（一种特异性小分子SCD抑制剂）抑制SCD活性会损害配体诱导的表皮生长因子（EGF）受体磷酸化，导致其下游靶点Akt、ERK和哺乳动物雷帕霉素靶点失活。重要的是，在SCD耗尽的癌细胞中，对EGF的促有丝分裂反应明显缺陷。表皮生长因子受体（EGFR）的SCD抑制促进的失活可能是由受体周围的脂质微环境的扰动引起的，因为我们检测到血浆脂质微区的横向流动性的显着改变。最后，肺癌细胞与SCD阻断剂的孵育增强了吉非替尼（一种用于癌症治疗的EGFR抑制剂）的抗生长作用。总之，我们的数据表明SCD活性可以通过调节EGFR -> Akt/ERK信号平台来控制癌细胞代谢、增殖和存活。我们的研究还表明SCD抑制剂作为肺癌的新型药理学药物的价值，肺癌是最常见和最致命的癌症形式之一，其治疗选择仍然非常有限。
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.