Chio, Iok In Christine, Jafarnejad, Seyed Mehdi, Ponz-Sarvise, Mariano, Park, Youngkyu, Rivera, Keith, Palm, Wilhelm, Wilson, John, Sangar, Vineet, Hao, Yuan, Öhlund, 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 (August 2016) NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell, 166 (4). pp. 963-976. ISSN 0092-8674
Abstract
Summary 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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > translation |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Signal Transduction CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Animal Shared Resource CSHL labs > Hammell M. lab CSHL labs > Pappin lab CSHL labs > Tuveson lab |
| Depositing User: | Matt Covey |
| Date: | 11 August 2016 |
| Date Deposited: | 04 Aug 2016 19:46 |
| Last Modified: | 08 Jul 2021 14:29 |
| PMCID: | PMC5234705 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33150 |
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