Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer
Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer
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DOI：
10.1158/1078-0432.ccr-15-0375
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发表时间：
2015-11-15
影响因子：
11.5
通讯作者：
Del Vecchio, Silvana
中科院分区：
文献类型：
--
作者：
De Rosa, Viviana;Iommelli, Francesca;Del Vecchio, Silvana
目的：癌细胞的标志之一是在常氧条件下葡萄糖过度转化为乳酸，也称为瓦尔堡效应。在这里，我们测试了EGFR的靶向抑制是否可以逆转这种效应并重新激活非小细胞肺癌（NSCLC）中的线粒体氧化磷酸化。实验设计：用一组EGFR或MET抑制剂处理敏感（HCC 827）和耐药（H1975和H1993）NSCLC细胞，然后测试EGFR信号传导、糖酵解级联和线粒体功能的变化。然后用靶向siRNA进行关键糖酵解酶的沉默。此外，荷瘤裸鼠与EGFR抑制剂进行了评估与F-18-FDG PET/CT和肿瘤进行了糖酵解和线粒体proteins.Results分析：有效抑制EGFR信号在NSCLC细胞诱导的己糖激酶II（HKII）和磷酸丙酮酸激酶M2（p-PKM 2，Tyr 105）的水平急剧下降，以及上调线粒体复合物亚基（OXPHOS）。因此，还观察到对EGFR抑制剂的响应中乳酸分泌减少和细胞内ATP水平增加。通过靶向siRNA转染下调HKII和PKM 2不会导致OXPHOS上调，但会增强EGFR TKI的作用。相反，选择性抑制AKT和ERK 1/2分别引起OXPHOS上调和糖酵解抑制。类似的发现，在肿瘤中得到适当的EGFR inhibitors.Conclusions治疗的动物：我们的研究结果表明，EGFR抑制剂可以重新激活氧化磷酸化的癌细胞，并提供了一个机制的线索，为合理组合的药物靶向EGFR依赖的增殖和糖代谢的癌症治疗。(C)2015年AACR。
Purpose: One of the hallmarks of cancer cells is the excessive conversion of glucose to lactate under normoxic conditions, also known as the Warburg effect. Here, we tested whether the targeted inhibition of EGFR may revert this effect and reactivate mitochondrial oxidative phosphorylation in non-small cell lung cancer (NSCLC).Experimental Design: Sensitive (HCC827) and resistant (H1975 and H1993) NSCLC cells were treated with a panel of EGFR or MET inhibitors, and then tested for changes of EGFR signaling, glycolytic cascade, and mitochondrial function. Silencing of key glycolytic enzymes was then performed with targeted siRNAs. Furthermore, tumor-bearing nude mice treated with EGFR inhibitors were evaluated with F-18-FDG PET/CT and tumors were analyzed for glycolytic and mitochondrial proteins.Results: Effective inhibition of EGFR signaling in NSCLC cells induced a dramatic reduction of hexokinase II (HKII) and phospho-pyruvate kinase M2 (p-PKM2, Tyr105) levels as well as an upregulation of mitochondrial complexes subunits (OXPHOS). Accordingly, a decreased lactate secretion and increased intracellular ATP levels were also observed in response to EGFR inhibitors. Downregulation of HKII and PKM2 by targeted siRNA transfection did not cause upregulation of OXPHOS but enhanced the effects of EGFR TKIs. Conversely, selective inhibition of AKT and ERK1/2 caused OXPHOS upregulation and glycolysis inhibition, respectively. Similar findings were obtained in tumors from animals treated with appropriate EGFR inhibitors.Conclusions: Our findings indicate that EGFR inhibitors may reactivate oxidative phosphorylation of cancer cells and provide a mechanistic clue for the rational combination of agents targeting EGFR-dependent proliferation and glucose metabolism in cancer therapy. (C) 2015 AACR.