J Biol Chem. 2014 Jul 25;289(30):20813-23. doi: 10.1074/jbc.M114.575464.
Genetic mutations in tumor cells cause several unique metabolic phenotypes that are critical for cancer cell proliferation. Mutations in the tyrosine kinase epidermal growth factor receptor (EGFR) induce oncogenic addiction in lung adenocarcinoma (LAD). However, the linkage between oncogenic mutated EGFR and cancer cell metabolism has not yet been clearly elucidated. Here we show that EGFR signaling plays an important role in aerobic glycolysis in EGFR-mutated LAD cells. EGFR-tyrosine kinase inhibitors (TKIs) decreased lactate production, glucose consumption, and the glucose-induced extracellular acidification rate (ECAR), indicating that EGFR signaling maintained aerobic glycolysis in LAD cells. Metabolomic analysis revealed that metabolites in the glycolysis, pentose phosphate pathway (PPP), pyrimidine biosynthesis, and redox metabolism were significantly decreased after treatment of LAD cells with EGFRTKI. On a molecular basis, the glucose transport carried out by glucose transporter 3 (GLUT3) was downregulated in TKI-sensitive LAD cells. Moreover, EGFR signaling activated carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the first step in de novo pyrimidine synthesis. We conclude that EGFR signaling regulates the global metabolic pathway in EGFR-mutated LAD cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, which is an attractive target for the development of more effective targeted therapies to treat patients with EGFR-mutated LAD.
肿瘤细胞中的基因突变导致了几种独特的代谢表型，这些表型对癌细胞的增殖至关重要。酪氨酸激酶表皮生长因子受体（EGFR）的突变导致肺腺癌（LAD）中的致癌成瘾。然而，致癌突变的 EGFR 与癌细胞代谢之间的联系尚未阐明。在这里，我们表明 EGFR 信号在 EGFR 突变的 LAD 细胞中的有氧糖酵解中发挥重要作用。EGFR 酪氨酸激酶抑制剂（TKI）降低了乳酸生成、葡萄糖消耗和葡萄糖诱导的细胞外酸化率（ECAR），表明 EGFR 信号维持了 LAD 细胞中的有氧糖酵解。代谢组学分析显示，在用 EGFRTKI 处理 LAD 细胞后，糖酵解、戊糖磷酸途径（PPP）、嘧啶生物合成和氧化还原代谢中的代谢物显著减少。从分子基础上讲，TKI 敏感的 LAD 细胞中葡萄糖转运蛋白 3（GLUT3）进行的葡萄糖转运被下调。此外，EGFR 信号激活了氨甲酰磷酸合成酶 2、天冬氨酸转氨甲酰酶和二氢乳清酸酶（CAD），它们催化从头嘧啶合成的第一步。我们得出结论，EGFR 信号调节 EGFR 突变的 LAD 细胞中的全局代谢途径。我们的数据提供了可能将治疗反应与代谢调节联系起来的证据，这是开发更有效的针对 EGFR 突变的 LAD 患者的靶向治疗方法的有吸引力的目标。
