Superoxide induced inhibition of death receptor signaling is mediated via induced expression of apoptosis inhibitory protein cFLIP.
CASP8 and FADD-Like Apoptosis Regulating Protein
/ genetics
Cell Line, Tumor
Cell Survival
Gene Expression Regulation, Neoplastic
Glycolysis
Humans
Lymphoma
/ genetics
Nitric Oxide
/ metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins c-bcl-2
/ genetics
Signal Transduction
Superoxides
/ metabolism
Up-Regulation
Apoptosis
Bcl-2
Cancer
Superoxide
cFLIP
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
08
10
2019
revised:
28
11
2019
accepted:
07
12
2019
pubmed:
19
1
2020
medline:
17
4
2021
entrez:
19
1
2020
Statut:
ppublish
Résumé
The death inhibitory proteins, cFLIP and Bcl-2, canonically act at different steps to regulate receptor-mediated apoptosis in cancer cells. Here we report that pharmacological or genetic means to effect an increase in intracellular superoxide result in cFLIP upregulation. Interestingly, Bcl-2 overexpression is associated with a concomitant increase in cFLIP, and reducing superoxide sensitizes Bcl-2 overexpressing cancer cells to receptor-mediated apoptosis via downregulation of cFLIP. Moreover, inhibiting glycolytic flux overcomes apoptosis resistance by superoxide-dependent downregulation of cFLIP. Superoxide-induced upregulation of cFLIP is a function of enhanced transcription, as evidenced by increases in cFLIP promoter activity and mRNA abundance. The positive effect of superoxide on cFLIP is mediated through its reaction with nitric oxide to generate peroxynitrite. Corroborating these findings in cell lines, subjecting primary cells derived from lymphoma patients to glucose deprivation ex vivo, as a means to decrease superoxide, not only reduced cFLIP expression but also significantly enhanced death receptor sensitivity. Based on this novel mechanistic insight into the redox regulation of cancer cell fate, modulation of intracellular superoxide could have potential therapeutic implications in cancers in which these two death inhibitory proteins present a therapeutic challenge.
Identifiants
pubmed: 31954371
pii: S2213-2317(19)31207-8
doi: 10.1016/j.redox.2019.101403
pmc: PMC6965745
pii:
doi:
Substances chimiques
BCL2 protein, human
0
CASP8 and FADD-Like Apoptosis Regulating Protein
0
CFLAR protein, human
0
Proto-Oncogene Proteins c-bcl-2
0
Superoxides
11062-77-4
Nitric Oxide
31C4KY9ESH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101403Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The Authors do not have any potential conflict of interest to disclose.
Références
Bioinformatics. 2013 Feb 1;29(3):347-54
pubmed: 23239672
J Biol Chem. 1998 Feb 27;273(9):5294-9
pubmed: 9478987
Cancer Res. 2006 Sep 15;66(18):8927-30
pubmed: 16982728
Exp Oncol. 2012 Oct;34(3):176-84
pubmed: 23070002
Oncogene. 2012 Nov 1;31(44):4677-88
pubmed: 22266862
J Biomed Sci. 2010 Apr 17;17:27
pubmed: 20398405
Biochemistry. 1998 May 19;37(20):7147-56
pubmed: 9585526
Free Radic Biol Med. 2010 Dec 15;49(12):1925-36
pubmed: 20937380
FEBS Lett. 1999 Oct 15;459(3):343-8
pubmed: 10526162
J Carcinog Mutagen. 2013;Suppl 6:
pubmed: 25379355
Cell. 1993 Dec 17;75(6):1169-78
pubmed: 7505205
Br J Haematol. 2005 Mar;128(6):767-73
pubmed: 15755279
EMBO J. 1995 Nov 15;14(22):5579-88
pubmed: 8521815
Cancer Metab. 2019 Jan 24;7:1
pubmed: 30697423
Oncogene. 2001 Sep 27;20(43):6263-8
pubmed: 11593437
Nature. 1997 Apr 3;386(6624):517-21
pubmed: 9087414
Antioxid Redox Signal. 2017 Aug 1;27(4):215-233
pubmed: 27927016
J Clin Pathol. 2016 Feb;69(2):122-7
pubmed: 26254281
J Biol Chem. 2013 May 3;288(18):12777-90
pubmed: 23519470
Free Radic Res. 2012 Aug;46(8):996-1003
pubmed: 22559302
FEBS Lett. 1998 Nov 27;440(1-2):13-8
pubmed: 9862415
EMBO J. 2002 Jul 15;21(14):3704-14
pubmed: 12110583
Redox Rep. 2001;6(4):211-4
pubmed: 11642710
J Immunol. 2008 Mar 1;180(5):3072-80
pubmed: 18292530
EMBO J. 1996 Jan 15;15(2):216-25
pubmed: 8617197
Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):5839-5848
pubmed: 29802228
Cancer Res. 1995 Jan 15;55(2):444-9
pubmed: 7812976
Int J Mol Sci. 2015 Dec 18;16(12):30321-41
pubmed: 26694384
Cell Death Differ. 2007 Sep;14(9):1617-27
pubmed: 17510660
Biochem Biophys Res Commun. 2002 Feb 1;290(4):1145-50
pubmed: 11811982
Cell Death Differ. 2006 Apr;13(4):628-41
pubmed: 16179939
Cancer Res. 2004 Feb 15;64(4):1452-9
pubmed: 14973069
Cancer Res. 2004 Nov 1;64(21):7867-78
pubmed: 15520193
Cell Death Differ. 2003 Nov;10(11):1273-85
pubmed: 12894215
Blood. 2008 Aug 1;112(3):690-8
pubmed: 18509086
Immunity. 2000 Jun;12(6):611-20
pubmed: 10894161
J Biol Chem. 2003 Apr 11;278(15):12759-68
pubmed: 12556444
J Cell Mol Med. 2003 Jan-Mar;7(1):49-56
pubmed: 12767261
Mol Cell Biol. 2001 Aug;21(16):5299-305
pubmed: 11463813
Br J Haematol. 2013 Jan;160(2):188-98
pubmed: 23167276
PLoS One. 2015 Mar 04;10(3):e0117994
pubmed: 25738497
J Immunol. 2016 Aug 1;197(3):923-33
pubmed: 27342840
Oncotarget. 2016 Dec 20;7(51):83964-83975
pubmed: 27863378
Ann N Y Acad Sci. 2003 Dec;1010:365-73
pubmed: 15033754
Antioxid Redox Signal. 2016 Aug 20;25(6):283-99
pubmed: 27400860
Immunity. 1995 Dec;3(6):673-82
pubmed: 8777713