NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

作者：Chio Iok In Christine; Jafarnejad Seyed Mehdi; Ponz Sarvise Mariano; Park Youngkyu; Rivera Keith; Palm Wilhelm; Wilson John; Sangar Vineet; Hao Yuan; Oehlund Daniel; Wright Kevin; Filippini Dea; Lee Eun Jung; Da Silva Brandon; Schoepfer Christina; Wilkinson John Erby; Buscaglia Jonathan M; DeNicola Gina M; Tiriac Herve; Hammell Molly; Crawford Howard C; Schmidt Edward E; Thompson Craig B; Pappin Darryl J; Sonenberg Nahum; Tuveson David A

来源：Cell, 2016, 166(4): 963-976.

DOI：10.1016/j.cell.2016.06.056

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 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 epidermal growth factor receptor (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.

• 出版日期2016-8-11