Mitochondrial STAT3 regulates antioxidant gene expression through complex I-derived NAD in triple negative breast cancer.
A549 Cells
Antioxidants
/ metabolism
Cell Line, Tumor
Electron Transport Complex I
/ genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Mitochondria
/ metabolism
NAD
/ genetics
Oxidation-Reduction
Reactive Oxygen Species
/ metabolism
STAT3 Transcription Factor
/ genetics
Signal Transduction
/ genetics
Triple Negative Breast Neoplasms
/ genetics
STAT3
breast cancer
glutathione
mitochondria
oxidative stress
reactive oxygen species
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
29
01
2021
received:
03
12
2020
accepted:
16
02
2021
pubmed:
20
2
2021
medline:
1
4
2022
entrez:
19
2
2021
Statut:
ppublish
Résumé
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor with roles in inflammation and tumorigenicity. A fraction of STAT3 localizes in mitochondria, where it augments tumorigenesis via regulation of mitochondrial functions, including modulation of respiration and redox status. We show a novel mechanism for mitochondrial STAT3 regulation of redox homeostasis in triple-negative breast cancer cells. Loss of STAT3 diminished complex I dehydrogenase activity and impaired NAD+ regeneration, leading to impaired expression of glutathione biosynthetic genes and other antioxidant genes. Expressing mitochondrially restricted STAT3 or replenishment of the cellular NAD pool restored antioxidant gene expression, as did complementation of the NADH dehydrogenase activity by expression of the STAT3-independent yeast dehydrogenase, NDI1. These NAD-regulated processes contributed to malignant phenotypes by promoting clonal cell growth and migration. Proximity interaction and protein pull-down assays identified three components of complex I that associated with mitochondrial STAT3, providing a potential mechanistic basis for how mitochondrial STAT3 affects complex I activity. Our data document a novel mechanism through which mitochondrial STAT3 indirectly controls antioxidant gene regulation through a retrograde NAD+ signal that is modulated by complex I dehydrogenase activity.
Identifiants
pubmed: 33605027
doi: 10.1002/1878-0261.12928
pmc: PMC8096790
doi:
Substances chimiques
Antioxidants
0
Reactive Oxygen Species
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
NAD
0U46U6E8UK
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1432-1449Subventions
Organisme : NCI NIH HHS
ID : P30 CA016087
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI028900
Pays : United States
Informations de copyright
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
PLoS One. 2010 Jul 22;5(7):e11707
pubmed: 20661474
Cell Metab. 2013 Aug 6;18(2):239-50
pubmed: 23931755
Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E468-E477
pubmed: 29282323
Cell. 2010 Nov 24;143(5):802-12
pubmed: 21094524
Int J Mol Sci. 2018 Jun 04;19(6):
pubmed: 29866996
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Front Mol Neurosci. 2019 Apr 26;12:108
pubmed: 31080405
Mitochondrion. 2007 Feb-Apr;7(1-2):106-18
pubmed: 17307400
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7607-12
pubmed: 16682634
Elife. 2017 Oct 02;6:
pubmed: 28967864
Annu Rev Genet. 2006;40:159-85
pubmed: 16771627
Genes Dev. 2016 Nov 1;30(21):2345-2369
pubmed: 27881599
Cell. 2008 Jul 11;134(1):112-23
pubmed: 18614015
J Clin Invest. 2002 May;109(9):1143-8
pubmed: 11994402
J Biol Chem. 2013 Oct 25;288(43):31280-8
pubmed: 24019511
EMBO J. 2016 Mar 15;35(6):618-34
pubmed: 26903601
BMC Bioinformatics. 2013 Apr 15;14:128
pubmed: 23586463
Front Physiol. 2017 Aug 24;8:595
pubmed: 28883796
Science. 2016 Jun 17;352(6292):1436-43
pubmed: 27127236
Biochim Biophys Acta. 2016 Jul;1857(7):902-14
pubmed: 26921811
Antioxid Redox Signal. 2007 Dec;9(12):2099-117
pubmed: 17822372
Cell Metab. 2010 Dec 1;12(6):654-61
pubmed: 21109197
J Invest Dermatol. 2014 Jul;134(7):1971-1980
pubmed: 24496235
PLoS One. 2012;7(11):e50644
pubmed: 23226344
Science. 2002 Mar 8;295(5561):1895-7
pubmed: 11847309
Front Cell Dev Biol. 2016 Oct 13;4:109
pubmed: 27790613
PLoS One. 2010 Mar 10;5(3):e9532
pubmed: 20224768
J Neurochem. 2003 Oct;87(2):448-60
pubmed: 14511122
Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):E8247-E8256
pubmed: 27930300
J Biol Chem. 2004 Feb 6;279(6):4127-35
pubmed: 14625276
PLoS One. 2011;6(8):e23295
pubmed: 21858060
Sci Signal. 2017 Mar 28;10(472):
pubmed: 28351946
Breast Cancer Res. 2013;15(4):R63
pubmed: 23938089
Elife. 2018 Jan 08;7:
pubmed: 29309036
Antioxid Redox Signal. 2013 Feb 1;18(4):386-99
pubmed: 22861165
PLoS One. 2013 Nov 29;8(11):e83395
pubmed: 24312439
J Biol Chem. 1999 Jun 18;274(25):17580-6
pubmed: 10364193
Cell. 1999 Aug 6;98(3):295-303
pubmed: 10458605
Int J Mol Sci. 2017 Dec 20;18(12):
pubmed: 29261130
Nat Rev Cancer. 2014 Nov;14(11):709-21
pubmed: 25342630
Nature. 2011 Jul 06;475(7354):106-9
pubmed: 21734707
Trends Cell Biol. 2016 Nov;26(11):804-817
pubmed: 27667171
J Biol Chem. 2011 Aug 26;286(34):29610-20
pubmed: 21715323
Biochem J. 2002 Dec 1;368(Pt 2):545-53
pubmed: 12180906
J Clin Invest. 2013 Mar;123(3):1068-81
pubmed: 23426180
J Biol Chem. 2010 Mar 5;285(10):7417-29
pubmed: 20042612
Nat Methods. 2013 Aug;10(8):730-6
pubmed: 23921808
Science. 2009 Feb 6;323(5915):793-7
pubmed: 19131594
Semin Immunol. 2014 Feb;26(1):20-8
pubmed: 24434063
J Cell Biol. 2018 Jul 2;217(7):2291-2298
pubmed: 29915025
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Endocr Rev. 2010 Apr;31(2):194-223
pubmed: 20007326
Front Pharmacol. 2019 Sep 19;10:1071
pubmed: 31607920
Mol Cell Biol. 2015 Nov;35(21):3646-56
pubmed: 26283727
Cell Metab. 2010 Dec 1;12(6):662-7
pubmed: 21109198
J Biol Chem. 2005 Apr 8;280(14):13560-7
pubmed: 15653680
Free Radic Res. 2010 May;44(5):479-96
pubmed: 20370557
Nat Rev Mol Cell Biol. 2012 Mar 07;13(4):225-238
pubmed: 22395773
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21836-41
pubmed: 21106760
Environ Health Perspect. 2008 Sep;116(9):1154-61
pubmed: 18795156
Cell Mol Life Sci. 2009 Dec;66(23):3663-73
pubmed: 19629388
Biochim Biophys Acta. 2010 Aug;1804(8):1666-75
pubmed: 19879981
Semin Radiat Oncol. 2019 Jan;29(1):6-15
pubmed: 30573185
J Biol Chem. 2011 Nov 11;286(45):38886-93
pubmed: 21937440
Biochim Biophys Acta. 2011 Nov;1813(11):1954-60
pubmed: 21396404
J Biol Chem. 2009 Aug 14;284(33):21872-21880
pubmed: 19553684
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52
pubmed: 18794531
Growth Factors. 2018 Apr;36(1-2):1-14
pubmed: 29873274
Biochemistry. 2010 Jan 19;49(2):304-11
pubmed: 20000467
Science. 2009 Jun 26;324(5935):1713-6
pubmed: 19556508
Cell Rep. 2018 Jun 5;23(10):2976-2988
pubmed: 29874584
J Cell Biol. 2002 Aug 19;158(4):647-57
pubmed: 12186850
Sci Rep. 2017 Nov 13;7(1):15388
pubmed: 29133922
Oncogene. 2017 Oct 19;36(42):5897-5909
pubmed: 28650465
Biochem Soc Trans. 2008 Oct;36(Pt 5):976-80
pubmed: 18793173
Biomolecules. 2019 Mar 27;9(4):
pubmed: 30934776
J Biol Chem. 2017 Aug 18;292(33):13500-13506
pubmed: 28687630
J Clin Invest. 2011 Jul;121(7):2723-35
pubmed: 21633165
Cancer Res. 2005 Feb 1;65(3):939-47
pubmed: 15705894
J Biol Chem. 2010 Jul 30;285(31):23532-6
pubmed: 20558729
iScience. 2020 Nov 18;23(12):101822
pubmed: 33305182
Mol Cell. 2010 Dec 22;40(6):893-904
pubmed: 21172655
J Exp Clin Cancer Res. 2019 May 14;38(1):195
pubmed: 31088482
Antioxid Redox Signal. 2013 Nov 1;19(13):1507-21
pubmed: 23461683
Front Oncol. 2017 May 04;7:85
pubmed: 28523248