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

Science Advances
Pallavi JainMarianne Koritzinsky

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.

References

Nov 26, 2002·Nature Cell Biology·Oscar Fernandez-CapetilloAndré Nussenzweig
May 7, 2003·The Journal of Biological Chemistry·Xiaosong WangBeverly Paigen
Mar 23, 2005·Current Opinion in Cell Biology·Sue Goo RheeHyun Ae Woo
Jan 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Einav GrossDeborah Fass
Jan 24, 2007·Physiological Reviews·Karen Bedard, Karl-Heinz Krause
Dec 25, 2008·The Biochemical Journal·Yoshihito IuchiJunichi Fujii
Jan 30, 2009·Cell Cycle·Dmitri WiederschainJohn D Benson
Oct 10, 2009·Nature Protocols·Mariusz R WieckowskiPaolo Pinton
Dec 30, 2009·The Journal of Clinical Investigation·Kasper M A RouschopBradly G Wouters
Jan 26, 2010·Antioxidants & Redox Signaling·Balázs EnyediMiklós Geiszt
Apr 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·Frank WeinbergNavdeep S Chandel
Jul 14, 2010·Autophagy·Ru Feng Wu, Lance S Terada
Jul 16, 2010·Journal of Cell Science·Timothy J Tavender, Neil J Bulleid
Oct 5, 2010·Respiratory Physiology & Neurobiology·Srikanth Pendyala, Viswanathan Natarajan
May 25, 2011·Nature Reviews. Cancer·William R Wilson, Michael P Hay
Apr 10, 2012·Nature Chemical Biology·Chuan-Xu LiuGuo-Qiang Chen
May 16, 2012·Cancer Discovery·Richard MarcotteJason Moffat
Sep 10, 2013·Seminars in Radiation Oncology·Marianne Koritzinsky, Bradly G Wouters
Nov 30, 2013·Nature Reviews. Drug Discovery·Chiara GorriniTak W Mak
Jan 24, 2014·Biochemical Society Transactions·Rachel E MartinNeil J Bulleid
May 17, 2014·Assay and Drug Development Technologies·Rasheena EdmondsonLiju Yang
May 23, 2014·Current Biology : CB·Michael Schieber, Navdeep S Chandel
Aug 26, 2014·Nature Reviews. Cancer·Miao Wang, Randal J Kaufman
Jan 22, 2015·Nucleic Acids Research·Matthew E RitchieGordon K Smyth
Feb 6, 2015·Free Radical Biology & Medicine·Ester Zito
Jun 13, 2015·Trends in Biochemical Sciences·Arden PerkinsP Andrew Karplus
Feb 26, 2016·Nature·Peter BaileySean M Grimmond
Apr 3, 2016·Experimental Biology and Medicine·Yong-Gang ZhangLianqin Li
May 25, 2016·Small GTPases·Peter Storz

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