Abstract PR03: NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer
Authors: Iok In Christine Chio, Seyed Mehdi Jafarnejad, Mariano Ponz-Sarvise, Youngkyu Park, Keith Rivera, Wilhelm Palm, Daniel Ohlund, Molly Hammell, Howard Crawford, Edward Schmidt, Craig Thompson, Darryl Pappin, Nahum Sonenberg, David Tuveson
Journal: Cancer Research (2017)

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is the 4th leading cause of cancer death in the USA. Lethality of PDA is largely ascribed to poor drug delivery and augmented cell survival pathways. We previously found that oncogenic Kras expression induced an important regulator of redox control, the transcription factor Nuclear factor erythroid-derived 2-like 2, Nfe2l2/Nrf2. Expression of Nrf2-dependent proteins is critical for neutralizing or eliminating toxicants and to maintain cellular redox homeostasis. The NRF2 transcriptional program is believed to protect neoplastic cells from oxidative stress, and may confer the resistance of these cells to chemotherapy. Thus, antagonizing NRF2 effector functions represents an attractive therapeutic strategy. Activation of Nrf2 leads to alterations in cellular redox levels, to which cysteine residues are particularly reactive. Redox modifications on reactive cysteines may regulate the activity of their corresponding protein, rendering these proteins as candidate redox-sensitive effectors of NRF2. To decipher changes in the cysteine proteome, we devised a highly sensitive proteomic method that combines a selectively cleavable cysteine-reactive affinity tag to enrich for and identify reduced cysteines, with amine-reactive isobaric tags for relative and absolute quantification of the total proteome. Using this approach, we identified cysteines on translational regulatory proteins to be explicitly oxidized in Nrf2-deficient, Kras mutant cells. Both cap-dependent and -independent mRNA translation was impaired in Nrf2-deficient pancreatic cancer cells, and can be rescued upon supplementation with antioxidants. In addition to stimulating translation through maintaining the reduced state of specific cysteine residues, redox regulation by Nrf2 also promotes EGFR autocrine signaling through AKT in KRAS mutant cells to fuel cap-dependent translation initiation. These functions converge to promote global protein synthesis in PDA. As a consequence, combined inhibition of AKT signaling and glutathione synthesis hampered the survival of PDA cells in vitro and in vivo, presenting a new opportunity for therapeutic intervention. This abstract is also being presented as Poster B31. Citation Format: Iok In Christine Chio, Seyed Mehdi Jafarnejad, Mariano Ponz-Sarvise, Youngkyu Park, Keith Rivera, Wilhelm Palm, Daniel Ohlund, Molly Hammell, Howard Crawford, Edward Schmidt, Craig Thompson, Darryl Pappin, Nahum Sonenberg, David Tuveson. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR03.