Signaling through the Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Axis Is Responsible for Aerobic Glycolysis mediated by Glucose Transporter in Epidermal Growth Factor Receptor (EGFR)-mutated Lung Adenocarcinoma.
Signaling through the Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Axis Is Responsible for Aerobic Glycolysis mediated by Glucose Transporter in Epidermal Growth Factor Receptor (EGFR)-mutated Lung Adenocarcinoma.
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DOI：
10.1074/jbc.m115.660498
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发表时间：
2015-07-10
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;Saruwatari K;Umemura S;Obata Y;Ishii G;Matsumoto S;Sugiyama E;Ochiai A;Abe R;Goto K;Esumi H;Tsuchihara K
背景：EGFR信号维持有氧糖酵解，但其分子机制尚不清楚。结果：药物抑制研究表明，通过PI 3 K途径的下游信号传导对葡萄糖转运和代谢至关重要。结论：PI 3 K信号通路调节EGFR突变型肺腺癌的关键代谢活动。意义：这些数据可以指导化疗方案的开发，包括靶向PI 3 K通路和葡萄糖转运蛋白机制。致癌性表皮生长因子受体（EGFR）信号传导在调节包括有氧糖酵解、戊糖磷酸途径（PPP）和嘧啶生物合成的总体代谢途径中起重要作用。然而，EGFR信号调节癌细胞代谢的分子机制仍不清楚。为了阐明EGFR信号传导如何与代谢活性相关，我们研究了RAS/MEK/ERK和PI 3 K/AKT/哺乳动物雷帕霉素靶蛋白（mTOR）通路对具有活化EGFR突变的肺腺癌（LAD）细胞系代谢改变的参与。虽然MEK抑制并没有改变乳酸的生产和细胞外酸化率，PI 3 K/mTOR抑制剂显着抑制EGFR突变型LAD细胞的糖酵解。此外，一项全面的代谢组学分析显示，葡萄糖6-磷酸和6-磷酸葡萄糖酸作为糖酵解和PPP中的早期代谢产物的水平在抑制PI 3 K/AKT/mTOR通路后降低，这表明PI 3 K信号传导与糖酵解中葡萄糖转运蛋白或己糖激酶的适当功能之间存在联系。事实上，PI 3 K/mTOR抑制有效地抑制了促进性葡萄糖转运蛋白1（GLUT 1）的膜定位，而GLUT 1则在细胞质中积累。最后，有氧糖酵解和细胞增殖下调时，GLUT 1基因的表达被RNAi抑制。综上所述，这些结果表明，PI 3 K/AKT/mTOR信号转导对于EGFR突变的LAD细胞中有氧糖酵解的调节是不可或缺的。
Background: EGFR signaling maintains aerobic glycolysis, but the molecular mechanism is still undefined. Results: Drug inhibition studies reveal that downstream signaling via the PI3K pathway is critical for glucose transport and metabolism. Conclusion: The PI3K signaling regulates key metabolic activities in EGFR-mutant lung adenocarcinoma. Significance: These data may guide the development of chemotherapeutic options, including targeting of the PI3K pathway and glucose transporter machinery. Oncogenic epidermal growth factor receptor (EGFR) signaling plays an important role in regulating global metabolic pathways, including aerobic glycolysis, the pentose phosphate pathway (PPP), and pyrimidine biosynthesis. However, the molecular mechanism by which EGFR signaling regulates cancer cell metabolism is still unclear. To elucidate how EGFR signaling is linked to metabolic activity, we investigated the involvement of the RAS/MEK/ERK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways on metabolic alteration in lung adenocarcinoma (LAD) cell lines with activating EGFR mutations. Although MEK inhibition did not alter lactate production and the extracellular acidification rate, PI3K/mTOR inhibitors significantly suppressed glycolysis in EGFR-mutant LAD cells. Moreover, a comprehensive metabolomics analysis revealed that the levels of glucose 6-phosphate and 6-phosphogluconate as early metabolites in glycolysis and PPP were decreased after inhibition of the PI3K/AKT/mTOR pathway, suggesting a link between PI3K signaling and the proper function of glucose transporters or hexokinases in glycolysis. Indeed, PI3K/mTOR inhibition effectively suppressed membrane localization of facilitative glucose transporter 1 (GLUT1), which, instead, accumulated in the cytoplasm. Finally, aerobic glycolysis and cell proliferation were down-regulated when GLUT1 gene expression was suppressed by RNAi. Taken together, these results suggest that PI3K/AKT/mTOR signaling is indispensable for the regulation of aerobic glycolysis in EGFR-mutated LAD cells.