NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.

Nature Metabolism
Douglas B FoxJames V Alvarez

Abstract

The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.

References

Aug 9, 2002·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Makoto KobayashiMasayuki Yamamoto
Jun 3, 2004·Cancer Research·Rebecca L ElstromCraig B Thompson
Jul 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Javier A MenendezRuth Lupu
Feb 19, 2005·Science·D D SarbassovDavid M Sabatini
Sep 20, 2005·Cancer Cell·Susan E MoodyLewis A Chodosh
Mar 2, 2006·Molecular Cell·Balasundaram PadmanabhanMasayuki Yamamoto
Nov 27, 2008·Proceedings of the National Academy of Sciences of the United States of America·David R WiseCraig B Thompson
Feb 3, 2009·The Journal of Biological Chemistry·Truyen NguyenCecil B Pickett
Mar 27, 2009·Carcinogenesis·Daniel A TennantEyal Gottlieb
Jun 10, 2010·Cancer Research·Tao JiangDonna D Zhang
Dec 15, 2010·Current Opinion in Genetics & Development·Christoph A Klein
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Mar 30, 2011·PloS One·Markus RingnérJohan Staaf
Jul 14, 2012·Cancer Cell·Yoichiro MitsuishiHozumi Motohashi
Jun 19, 2013·Oncogene·X WangD S Conklin
Dec 7, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ulrike A KöhlerSabine Werner
Dec 11, 2013·Cancer Research·Bridgid E HastMichael B Major
Dec 18, 2013·Science·Ophir ShalemFeng Zhang
Jan 15, 2014·Analytical Chemistry·Xiaojing LiuJason W Locasale
May 3, 2014·Cancer Discovery·Yi FengLewis A Chodosh
Jul 31, 2014·Nature Methods·Neville E SanjanaFeng Zhang
Aug 15, 2014·Nature Reviews. Cancer·María Soledad SosaJulio A Aguirre-Ghiso
Jan 30, 2015·Nucleic Acids Research·Andrew N Lane, Teresa W-M Fan
Mar 17, 2015·Nature Cell Biology·Lindsey K Boroughs, Ralph J DeBerardinis
Sep 12, 2015·Cancer Research·Albert C Yeh, Sridhar Ramaswamy
Oct 16, 2015·Nature·Elena PiskounovaSean J Morrison
Oct 21, 2015·Nature Genetics·Gina M DeNicolaLewis C Cantley
Jan 16, 2016·Cell Systems·Arthur LiberzonPablo Tamayo
Jan 16, 2016·Cell Metabolism·Natalya N Pavlova, Craig B Thompson
Apr 15, 2016·Science Translational Medicine·Hui WangHongting Zheng
Jul 13, 2016·Nature Communications·Geneviève DebloisVincent Giguère
Mar 24, 2017·Nature Protocols·Julia JoungFeng Zhang
Apr 22, 2017·Trends in Molecular Medicine·Iok In Christine Chio, David A Tuveson
May 16, 2017·The Journal of Clinical Investigation·Kristina M HavasMartin Jechlinger
Jun 14, 2017·Nature·Haizhen WangPiotr Sicinski

❮ Previous
Next ❯

Citations

Oct 22, 2020·Cancers·Janine M DeBlasi, Gina M DeNicola
Jan 7, 2021·Antioxidants & Redox Signaling·Emiliano Panieri, Luciano Saso
Dec 17, 2020·Frontiers in Oncology·Jiangang ZhaoJian Hu
Feb 15, 2021·Seminars in Cancer Biology·Stefan WernerKlaus Pantel
Feb 7, 2021·International Journal of Molecular Sciences·Nadine Abdel HadiAlice Carrier
Mar 24, 2021·Archives of Pharmacal Research·Bo-Hyun ChoiMi-Kyoung Kwak
Jul 3, 2021·Oxidative Medicine and Cellular Longevity·Liduo YueLihong Fan
Jul 15, 2021·IScience·Ronen HazanMichael Klutstein
Jul 24, 2021·Scientific Reports·Rachel NewcombJames V Alvarez
Aug 4, 2021·Trends in Endocrinology and Metabolism : TEM·Yi LiuShuang Tang
Jul 11, 2020·Cancer Cell·John D HayesKenneth D Tew
Sep 9, 2021·The FEBS Journal·Anna ZoccaratoAjay M Shah
Nov 14, 2020·Cell·Shensi ShenCaroline Robert
Oct 26, 2021·Molecular Systems Biology·Ksenija Radic ShechterMartin Jechlinger
Oct 26, 2021·Reviews in Medical Virology·Alfredo Cruz-GregorioJosé Pedraza-Chaverri
Oct 27, 2021·Cancer Biology & Therapy·Vinod S BishtKiran Ambatipudi
Aug 20, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Avani VyasUmamaheswar Duvvuri

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE7390

Methods Mentioned

BETA
transgenic
reverse-transcription PCR
enzymatic dissociation
scraping
PCR
restriction digest
flow cytometry
Fluorescence
transfection

Software Mentioned

GUIDES
ImageJ
MAGeCK
GlobalTest
GSEA
Prism
CellProfiler
GraphPad
MetaboAnalyst
GlobalAncova

Related Concepts

Related Feeds

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.

Cancer Metabolic Reprogramming (Keystone)

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.

Cancer Metabolic Reprogramming

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.