NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer.
NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer.
复制标题
DOI：
10.1016/j.cell.2016.06.056
复制
发表时间：
2016-08-11
期刊：
影响因子：
64.5
通讯作者：
Tuveson DA
中科院分区：
文献类型：
--
作者：
Chio IIC;Jafarnejad SM;Ponz-Sarvise M;Park Y;Rivera K;Palm W;Wilson J;Sangar V;Hao Y;Öhlund D;Wright K;Filippini D;Lee EJ;Da Silva B;Schoepfer C;Wilkinson JE;Buscaglia JM;DeNicola GM;Tiriac H;Hammell M;Crawford HC;Schmidt EE;Thompson CB;Pappin DJ;Sonenberg N;Tuveson DA
胰腺癌是一种致命的恶性肿瘤，缺乏有效的治疗方法。我们之前报道过致癌的 Kras 诱导氧化还原主调节因子 Nrf2/Nfe2l2 刺激胰腺癌和肺癌的发生。在这里，我们证明 NRF2 通过调节 mRNA 翻译对于维持胰腺癌增殖是必需的。具体来说，NRF2 的缺失导致自分泌 EGFR 信号传导缺陷和特定翻译调节蛋白的氧化，从而导致胰腺癌细胞中帽依赖性和帽非依赖性 mRNA 翻译受损。联合靶向 EGFR 效应器 AKT 和谷胱甘肽抗氧化途径模拟 Nrf2 消融，在离体和体内有效抑制胰腺癌，代表了一种有前途的治疗该疾病的合成致死策略。
Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nrf2/Nfe2l2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine EGFR signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.