| Literature DB >> 27477511 |
Iok In Christine Chio1, Seyed Mehdi Jafarnejad2, Mariano Ponz-Sarvise1, Youngkyu Park1, Keith Rivera3, Wilhelm Palm4, John Wilson3, Vineet Sangar5, Yuan Hao3, Daniel Öhlund1, Kevin Wright1, Dea Filippini1, Eun Jung Lee1, Brandon Da Silva1, Christina Schoepfer1, John Erby Wilkinson6, Jonathan M Buscaglia7, Gina M DeNicola8, Herve Tiriac1, Molly Hammell3, Howard C Crawford6, Edward E Schmidt9, Craig B Thompson4, Darryl J Pappin3, Nahum Sonenberg2, David A Tuveson10.
Abstract
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.Entities:
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Year: 2016 PMID： 27477511 PMCID： PMC5234705 DOI： 10.1016/j.cell.2016.06.056
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582