Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma.
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DOI：
10.1074/jbc.m114.575464
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发表时间：
2014-07-25
期刊：
影响因子：
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通讯作者：
Tsuchihara K
中科院分区：
文献类型：
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作者：
Makinoshima H;Takita M;Matsumoto S;Yagishita A;Owada S;Esumi H;Tsuchihara K
背景：癌症驱动基因的基因突变诱导癌细胞特异性代谢改变。结果：EGF受体信号在egfr突变肺癌的糖酵解、戊糖磷酸途径和嘧啶生物合成中起重要作用。结论：我们的工作揭示了EGFR信号轴与关键代谢变化之间的关系。意义：这些数据暗示egfr突变LAD的治疗反应和代谢调节之间可能存在联系。肿瘤细胞中的基因突变导致几种独特的代谢表型，这些代谢表型对癌细胞增殖至关重要。酪氨酸激酶表皮生长因子受体（EGFR）突变诱导肺腺癌（LAD）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清楚阐明。在这里，我们发现EGFR信号在EGFR突变的LAD细胞的有氧糖酵解中起重要作用。EGFR-酪氨酸激酶抑制剂（TKIs）降低乳酸生成、葡萄糖消耗和葡萄糖诱导的细胞外酸化率（ECAR），表明EGFR信号传导维持了LAD细胞的有氧糖酵解。代谢组学分析显示，EGFR-TKI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的代谢物显著减少。在分子基础上，葡萄糖转运蛋白3 （GLUT3）进行的葡萄糖转运在tki敏感的LAD细胞中下调。此外，EGFR信号传导激活氨甲酰磷酸合成酶2、天冬氨酸转氨基甲酰基酶和二氢化酶（CAD），这些酶催化了从头合成嘧啶的第一步。我们得出结论，EGFR信号调节EGFR突变的LAD细胞的整体代谢途径。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，这是开发更有效的靶向治疗方法来治疗egfr突变LAD患者的一个有吸引力的靶点。
Background: Genetic mutations in cancer-driver genes induce specific metabolic alterations in cancer cells. Results: EGF receptor signaling has an important role for glycolysis, pentose phosphate pathway, and pyrimidine biosynthesis in EGFR-mutated lung cancer. Conclusion: Our work reveals the relationship between the EGFR signaling axis and key metabolic changes. Significance: These data implicate a possible link between therapeutic response and regulation of metabolism in EGFR-mutated LAD. 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 EGFR-TKI. 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.