NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4

Pallavi Jain, Anna Dvorkin-Gheva, Erik Mollen, Lucie Malbeteau, Michael Xie, Fatima Jessa, Piriththiv Dhavarasa, Stephen Chung, Kevin R. Brown, Gun Ho Jang, Parth Vora, Faiyaz Notta, Jason Moffat, David Hedley, Paul C. Boutros, Bradly G. Wouters, Marianne Koritzinsky*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article numbereabf7114
Number of pages13
JournalScience advances
Volume7
Issue number19
DOIs
Publication statusPublished - May 2021

Keywords

  • CELLS
  • CHECKPOINT ACTIVATION
  • DNA-DAMAGE
  • H2O2
  • HYDROGEN-PEROXIDE
  • INHIBITOR
  • OXIDASE
  • OXIDATIVE STRESS
  • PEROXIREDOXIN
  • TUMOR

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