@article{acba80d3a9b84171adc36fccf0d15caf,
title = "NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4",
abstract = "There is an urgent need to identify vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). PDAC cells acquire metabolic changes that augment NADPH production and cytosolic redox homeostasis. Here, we show that high NADPH levels drive activity of NADPH oxidase 4 (NOX4) expressed in the endoplasmic reticulum (ER) membrane. NOX4 produces H2O2 metabolized by peroxiredoxin 4 (PRDX4) in the ER lumen. Using functional genomics and subsequent in vitro and in vivo validations, we find that PDAC cell lines with high NADPH levels are dependent on PRDX4 for their growth and survival. PRDX4 addiction is associated with increased reactive oxygen species, a DNA-PKcs-governed DNA damage response and radiosensitivity, which can be rescued by depletion of NOX4 or NADPH. Hence, this study has identified NOX4 as a protein that paradoxically converts the reducing power of the cytosol to an ER-specific oxidative stress vulnerability in PDAC that may be therapeutically exploited by targeting PRDX4.",
keywords = "CELLS, CHECKPOINT ACTIVATION, DNA-DAMAGE, H2O2, HYDROGEN-PEROXIDE, INHIBITOR, OXIDASE, OXIDATIVE STRESS, PEROXIREDOXIN, TUMOR",
author = "Pallavi Jain and Anna Dvorkin-Gheva and Erik Mollen and Lucie Malbeteau and Michael Xie and Fatima Jessa and Piriththiv Dhavarasa and Stephen Chung and Brown, {Kevin R.} and Jang, {Gun Ho} and Parth Vora and Faiyaz Notta and Jason Moffat and David Hedley and Boutros, {Paul C.} and Wouters, {Bradly G.} and Marianne Koritzinsky",
note = "Funding Information: Funding for this work was provided by the Cancer Research Society/Robert Lutterman Memorial Fund (Operating Grant #21322 to M.K., D.H., and P.C.B.), The Terry Fox Foundation/Research Institute (New Frontiers Research Program PPG09-020005 to M.K., B.G.W., and D.H.), The Princess Margaret Cancer Foundation (Invest in Research award to M.K., Postdoctoral Fellowship to P.J., and Postdoctoral Fellowship from the George Knudson Memorial Fellowship Fund to L.M.), the Strategic Training in Translational Radiation Medicine for the 21st Century (STARS21) Program (Fellowship to P.J.), the NIH/NCI (P30CA016042 to P.C.B.), and the Ontario Ministry of Health and Princess Margaret Cancer Centre. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",
year = "2021",
month = may,
doi = "10.1126/sciadv.abf7114",
language = "English",
volume = "7",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "19",
}