Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, South Korea.
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Cancer Res. 2018 Aug 15;78(16):4482-4496. doi: 10.1158/0008-5472.CAN-18-0117. Epub 2018 Jun 26.
Oncogenic EGFR is essential for the development and growth of non-small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs. Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. .
致癌性 EGFR 对于非小细胞肺癌（NSCLC）的发展和生长至关重要，但 EGFR 在肺癌代谢中的确切作用仍不清楚。在这里，我们表明，EGFR 突变介导的糖酵解增强对于 EGFR 稳定性至关重要。EGFR 敲低通过对糖酵解基因的转录调控显著降低了糖酵解途径中间产物的水平。EGFR 突变增强的糖酵解对于为三羧酸循环提供燃料是必需的，三羧酸循环是 EGFR 稳定性的关键组成部分。非持续的 ATP 产生会增加活性氧物质的积累，随后 JNK 介导的自噬激活，进而诱导 EGFR 降解。我们的数据表明，EGFR 突变型 NSCLC 细胞需要 EGFR 突变增强的糖酵解来维持 EGFR 的稳定性。该途径可能成为 EGFR 突变型 NSCLC 的有吸引力的治疗靶点。EGFR 突变增强的糖酵解通过抑制 JNK 诱导的自噬来维持 EGFR 水平。这为在 EGFR 突变型 NSCLC 患者中使用 JNK 激活剂提供了有希望的依据。
