SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis.
PSD
SMAC/Diablo
cancer
mitochondria
phosphatidylethanolamine synthesis
phospholipids
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
26
01
2021
received:
02
11
2020
accepted:
31
03
2021
pubmed:
2
4
2021
medline:
8
4
2022
entrez:
1
4
2021
Statut:
ppublish
Résumé
SMAC/Diablo, a pro-apoptotic protein, yet it is overexpressed in several cancer types. We have described a noncanonical function for SMAC/Diablo as a regulator of lipid synthesis during cancer cell proliferation and development. Here, we explore the molecular mechanism through which SMAC/Diablo regulates phospholipid synthesis. We showed that SMAC/Diablo directly interacts with mitochondrial phosphatidylserine decarboxylase (PSD) and inhibits its catalytic activity during synthesis of phosphatidylethanolamine (PE) from phosphatidylserine (PS). Unlike other phospholipids (PLs), PE is synthesized not only in the endoplasmic reticulum but also in mitochondria. As a result, PSD activity and mitochondrial PE levels were increased in the mitochondria of SMAC/Diablo-deficient cancer cells, with the total amount of cellular PLs and phosphatidylcholine (PC) being lower as compared to SMAC-expressing cancer cells. Moreover, in the absence of SMAC/Diablo, PSD inhibited cancer cell proliferation by catalysing the overproduction of mitochondrial PE and depleting the cellular levels of PC, PE and PS. Additionally, we demonstrated that both SMAC/Diablo and PSD colocalization in the nucleus resulted in increased levels of nuclear PE, that acts as a signalling molecule in regulating several nuclear activities. By using a peptide array composed of 768-peptides derived from 11 SMAC-interacting proteins, we identified six nuclear proteins ARNT, BIRC2, MAML2, NR4A1, BIRC5 and HTRA2 Five of them also interacted with PSD through motifs that are not involved in SMAC binding. Synthetic peptides carrying the PSD-interacting motifs of these proteins could bind purified PSD and inhibit the PSD catalytic activity. When targeted specifically to the mitochondria or the nucleus, these synthetic peptides inhibited cancer cell proliferation. To our knowledge, these are the first reported inhibitors of PSD acting also as inhibitors of cancer cell proliferation. Altogether, we demonstrated that phospholipid metabolism and PE synthesis regulated by the SMAC-PSD interaction are essential for cancer cell proliferation and may be potentially targeted for treating cancer.
Identifiants
pubmed: 33794068
doi: 10.1002/1878-0261.12959
pmc: PMC8564633
doi:
Substances chimiques
Apoptosis Regulatory Proteins
0
DIABLO protein, human
0
Intracellular Signaling Peptides and Proteins
0
Mitochondrial Proteins
0
Phosphatidylethanolamines
0
phosphatidylethanolamine
39382-08-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3037-3061Informations de copyright
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Nat Rev Drug Discov. 2005 Jul;4(7):594-610
pubmed: 16052242
J Cell Biol. 2000 Jun 12;149(6):1215-24
pubmed: 10851019
Nature. 2017 Mar 30;543(7647):681-686
pubmed: 28329758
J Biol Chem. 2008 Jul 18;283(29):20320-9
pubmed: 18499667
J Diabetes Res. 2018 Jun 14;2018:9363461
pubmed: 30013988
J Cell Sci. 2004 Jun 1;117(Pt 13):2805-12
pubmed: 15169837
J Membr Biol. 2015 Apr;248(2):301-7
pubmed: 25572835
J Biol Chem. 2016 Feb 12;291(7):3658-67
pubmed: 26663081
Nat Genet. 2018 Feb;50(2):219-228
pubmed: 29335542
FASEB J. 1995 Apr;9(7):484-96
pubmed: 7737456
Nature. 2011 May 26;473(7348):528-31
pubmed: 21532591
Biochim Biophys Acta. 1998 Dec 8;1436(1-2):201-32
pubmed: 9838115
J Biol Chem. 1990 May 5;265(13):7248-56
pubmed: 2332429
Mol Cell Biol. 2002 Nov;22(21):7688-700
pubmed: 12370315
Mass Spectrom Rev. 2018 Mar;37(2):107-138
pubmed: 27276657
Biochem Cell Biol. 2012 Apr;90(2):188-99
pubmed: 22339418
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Nat Methods. 2006 Dec;3(12):995-1000
pubmed: 17072308
Amino Acids. 2011 Nov;41(5):1071-9
pubmed: 21573677
Mol Microbiol. 2009 May;72(4):1068-79
pubmed: 19400804
Mol Ther. 2018 Mar 7;26(3):680-694
pubmed: 29396267
FASEB J. 2015 Nov;29(11):4589-99
pubmed: 26195590
Cell Stem Cell. 2019 Jun 6;24(6):1007
pubmed: 31173706
J Invest Dermatol. 1999 Nov;113(5):838-42
pubmed: 10571742
Cell Metab. 2006 May;3(5):321-31
pubmed: 16679290
Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24
pubmed: 18216768
J Biol Chem. 1994 Nov 4;269(44):27494-502
pubmed: 7961664
Nat Rev Mol Cell Biol. 2010 Aug;11(8):593-8
pubmed: 20606693
Cell. 2000 Jul 7;102(1):43-53
pubmed: 10929712
Adv Enzyme Regul. 2011;51(1):91-9
pubmed: 21035491
Crit Rev Biochem Mol Biol. 2011 Oct;46(5):436-57
pubmed: 21913876
Biol Cell. 2004 Oct;96(8):657-67
pubmed: 15519699
Front Pharmacol. 2017 Jan 23;8:12
pubmed: 28167913
Cell. 2000 Jul 7;102(1):33-42
pubmed: 10929711
J Cell Sci. 1993 Mar;104 ( Pt 3):853-9
pubmed: 8314878
J Lipid Res. 2016 Jan;57(1):6-24
pubmed: 26563290
Cell Death Differ. 2017 Jul;24(7):1137-1139
pubmed: 28475178
J Biol Chem. 1957 May;226(1):497-509
pubmed: 13428781
NMR Biomed. 1999 Nov;12(7):413-39
pubmed: 10654290
FEBS J. 2013 Dec;280(24):6295-310
pubmed: 24112514
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Jan;1862(1):25-38
pubmed: 27650064
Bioorg Med Chem. 2010 May 15;18(10):3564-9
pubmed: 20430627
Cell Death Differ. 2008 Mar;15(3):453-60
pubmed: 18174901
Dis Model Mech. 2013 Nov;6(6):1353-63
pubmed: 24203995
Int Rev Cell Mol Biol. 2016;321:29-88
pubmed: 26811286
J Biol Chem. 2018 Feb 2;293(5):1493-1503
pubmed: 29247006
J Biol Chem. 1999 Apr 30;274(18):12339-45
pubmed: 10212204
J Cancer Res Clin Oncol. 2008 May;134(5):543-50
pubmed: 17922292
Bioelectrochemistry. 2002 Nov;58(1):13-21
pubmed: 12401566
Cell. 2014 Jul 3;158(1):84-97
pubmed: 24995980
Mol Cell. 2017 Jul 20;67(2):252-265.e6
pubmed: 28689661
Arch Biochem Biophys. 1983 Jun;223(2):484-94
pubmed: 6859873
J Biochem. 1995 May;117(5):1095-9
pubmed: 8586625
J Lipid Res. 2008 Jul;49(7):1377-87
pubmed: 18204094
Cancer Res. 2005 Jan 1;65(1):210-8
pubmed: 15665297
Oxid Med Cell Longev. 2017;2017:4829180
pubmed: 28785375
Cell Rep. 2017 Jan 17;18(3):647-658
pubmed: 28099844
Mol Microbiol. 2016 Mar;99(6):999-1014
pubmed: 26585333
APMIS. 2003 Mar;111(3):382-8
pubmed: 12752217
Cell Death Differ. 2015 Mar;22(3):499-508
pubmed: 25571976
Cell Rep. 2018 Aug 28;24(9):2404-2417.e8
pubmed: 30157433
EMBO J. 2007 Mar 21;26(6):1713-25
pubmed: 17332748
Biochim Biophys Acta. 2013 Mar;1831(3):543-54
pubmed: 22960354
Elife. 2016 Jul 12;5:
pubmed: 27403889
Oncotarget. 2017 Nov 6;8(62):105492-105509
pubmed: 29285267
Eur J Biochem. 1999 Sep;264(2):545-53
pubmed: 10491102
Proc Natl Acad Sci U S A. 2017 May 23;114(21):5431-5436
pubmed: 28396409
J Biol Chem. 2013 Feb 8;288(6):4158-73
pubmed: 23250747
Cell Biol Int. 1996 Jun;20(6):407-12
pubmed: 8858825
Nat Commun. 2010 Oct 19;1:100
pubmed: 20981028
Biochim Biophys Acta. 2014 Apr 4;1841(4):595-609
pubmed: 24316057
J Biol Chem. 2005 Dec 2;280(48):40032-40
pubmed: 16192276
Biochemistry. 2002 Aug 6;41(31):9813-23
pubmed: 12146947
Anal Biochem. 2005 Oct 1;345(1):2-9
pubmed: 15950911
FEBS J. 2013 Dec;280(24):6311-21
pubmed: 23890371
AAPS J. 2006 May 05;8(2):E314-21
pubmed: 16796382