Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis.
Carcinoma, Pancreatic Ductal
/ genetics
Carrier Proteins
/ metabolism
Humans
Membrane Proteins
/ metabolism
Methionine
Methionine Sulfoxide Reductases
/ chemistry
Oxidation-Reduction
Pancreatic Neoplasms
/ genetics
Pyruvate Kinase
/ metabolism
Thyroid Hormones
/ metabolism
Thyroid Hormone-Binding Proteins
Pancreatic Neoplasms
PKM2
cancer metabolism
glucose oxidation
metastasis
methionine oxidation
pancreatic cancer
redox signaling
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 08 2022
18 08 2022
Historique:
received:
07
10
2021
revised:
06
04
2022
accepted:
02
06
2022
pubmed:
26
6
2022
medline:
24
8
2022
entrez:
25
6
2022
Statut:
ppublish
Résumé
Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.
Identifiants
pubmed: 35752173
pii: S1097-2765(22)00541-X
doi: 10.1016/j.molcel.2022.06.005
pmc: PMC9391305
mid: NIHMS1816254
pii:
doi:
Substances chimiques
Carrier Proteins
0
Membrane Proteins
0
Thyroid Hormones
0
Methionine
AE28F7PNPL
Methionine Sulfoxide Reductases
EC 1.8.4.-
Pyruvate Kinase
EC 2.7.1.40
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3045-3060.e11Subventions
Organisme : NCI NIH HHS
ID : R01 CA267870
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240654
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM139245
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127297
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211462
Pays : United States
Organisme : NIH HHS
ID : S10 OD021801
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA210240
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests C.J.C., F.D.T., and A.H.C. are inventors on patent applications related to the redox-active reagents for methionine conjugation. C.J.T. is listed as an inventor on patents related to PKM2 activators. The remaining authors declare no competing interests.
Références
Nucleic Acids Res. 2019 Jan 8;47(D1):D590-D595
pubmed: 30321428
Cell. 2015 Jan 15;160(1-2):324-38
pubmed: 25557080
Semin Cell Dev Biol. 2015 Jul;43:43-51
pubmed: 26277545
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18628-33
pubmed: 20937881
Biochem J. 2016 Mar 15;473(6):703-15
pubmed: 26699902
Cancers (Basel). 2019 Jun 19;11(6):
pubmed: 31248212
Nat Methods. 2017 May;14(5):513-520
pubmed: 28394336
Nat Methods. 2007 Mar;4(3):207-14
pubmed: 17327847
Acta Biochim Pol. 1997;44(4):711-24
pubmed: 9584851
Sci Signal. 2009 Nov 17;2(97):ra73
pubmed: 19920251
Elife. 2019 Jul 02;8:
pubmed: 31264961
Nat Methods. 2022 Mar;19(3):341-352
pubmed: 35228727
Cell. 2019 Apr 18;177(3):711-721.e8
pubmed: 30982603
Cell Metab. 2011 Sep 7;14(3):415-27
pubmed: 21907146
Nat Biotechnol. 2012 Oct;30(10):918-20
pubmed: 23051804
J Bacteriol. 1995 Feb;177(3):502-7
pubmed: 7836279
Structure. 2007 Aug;15(8):992-1004
pubmed: 17683942
Biosci Rep. 2013 Feb 05;33(2):e00021
pubmed: 23216091
Circ Res. 2008 Feb 15;102(3):273-4
pubmed: 18276922
Nature. 2008 Mar 13;452(7184):230-3
pubmed: 18337823
Cell Death Dis. 2018 Feb 7;9(2):161
pubmed: 29415987
Oxid Med Cell Longev. 2016;2016:4350965
pubmed: 26998193
J Am Chem Soc. 2019 Aug 14;141(32):12657-12662
pubmed: 31361488
Cancer Biol Ther. 2009 Jul;8(14):1378-85
pubmed: 19556849
Nature. 2008 Mar 13;452(7184):181-6
pubmed: 18337815
Nat Rev Cancer. 2021 Mar;21(3):162-180
pubmed: 33462499
ACS Cent Sci. 2020 Jan 22;6(1):32-40
pubmed: 31989024
Cancer Cell. 2018 Mar 12;33(3):355-367.e7
pubmed: 29533781
Nat Chem Biol. 2012 Oct;8(10):839-47
pubmed: 22922757
Curr Opin Cell Biol. 2006 Dec;18(6):598-608
pubmed: 17046224
Cancer Cell. 2005 May;7(5):469-83
pubmed: 15894267
Dev Cell. 2019 Feb 11;48(3):313-328.e8
pubmed: 30686527
Science. 2017 Feb 10;355(6325):597-602
pubmed: 28183972
Nat Biotechnol. 2013 Sep;31(9):827-32
pubmed: 23873081
BMC Cancer. 2007 Sep 04;7:172
pubmed: 17784942
Cell. 2015 Jul 30;162(3):540-51
pubmed: 26232224
Nature. 2011 Jul 06;475(7354):106-9
pubmed: 21734707
Nature. 2012 Nov 15;491(7424):458-462
pubmed: 23064226
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):5733-5740
pubmed: 32123103
Biochem Biophys Res Commun. 2017 Feb 26;484(1):189-194
pubmed: 28104395
Trends Biochem Sci. 2012 Aug;37(8):309-16
pubmed: 22626471
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
Cell. 2016 Aug 11;166(4):963-976
pubmed: 27477511
Cell. 2019 Jul 11;178(2):330-345.e22
pubmed: 31257027
Antioxid Redox Signal. 2003 Oct;5(5):577-82
pubmed: 14580313
Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):
pubmed: 33622793
J Ocul Biol Dis Infor. 2009 Dec 12;2(4):223-234
pubmed: 20157357
Cell Rep. 2014 Aug 7;8(3):754-66
pubmed: 25066121
Nature. 2015 Nov 12;527(7577):186-91
pubmed: 26466563
Elife. 2014 Jul 09;3:
pubmed: 25009227
Oncogenesis. 2020 May 15;9(5):51
pubmed: 32415061
Science. 2011 Dec 2;334(6060):1278-83
pubmed: 22052977
Science. 2011 Dec 23;334(6063):1710-3
pubmed: 22116028
Nature. 2018 Apr 4;556(7699):135
pubmed: 29620732
Elife. 2019 Dec 16;8:
pubmed: 31841108
EMBO J. 2013 Oct 16;32(20):2708-21
pubmed: 24045232
Cancer Discov. 2018 Sep;8(9):1112-1129
pubmed: 29853643
Semin Cancer Biol. 2005 Aug;15(4):300-8
pubmed: 15908230
Methods Mol Biol. 2007;358:177-97
pubmed: 17035687
Chem Rev. 2013 Jul 10;113(7):4633-79
pubmed: 23514336
Nat Commun. 2016 Dec 19;7:13730
pubmed: 27991488
Rapid Commun Mass Spectrom. 2004;18(18):2162-8
pubmed: 15317041
Mol Cell Proteomics. 2017 May;16(5):873-890
pubmed: 28325852
J Biol Chem. 2017 Apr 28;292(17):7189-7207
pubmed: 28270511
Proteomics. 2013 Jan;13(1):22-4
pubmed: 23148064
Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8638-43
pubmed: 26124089
FASEB J. 2009 Feb;23(2):464-72
pubmed: 18845767
Cell. 2013 Oct 10;155(2):397-409
pubmed: 24120138
Mol Cell. 2013 Aug 8;51(3):397-404
pubmed: 23911929
Cell. 2017 Aug 24;170(5):875-888.e20
pubmed: 28757253
Cell Metab. 2021 May 4;33(5):1013-1026.e6
pubmed: 33609439
Antioxid Redox Signal. 2005 May-Jun;7(5-6):560-77
pubmed: 15890001
PLoS One. 2013 May 21;8(5):e63402
pubmed: 23704904
Mol Biol Cell. 2004 Mar;15(3):1055-64
pubmed: 14699060
Nucleic Acids Res. 2015 Feb 27;43(4):2466-85
pubmed: 25628363
Nat Biotechnol. 2015 Jun;33(6):661-7
pubmed: 25961408
Stat Appl Genet Mol Biol. 2004;3:Article3
pubmed: 16646809
Cell. 2008 May 2;133(3):462-74
pubmed: 18455987
Cell. 2015 Jul 30;162(3):552-63
pubmed: 26232225
Nat Cell Biol. 2014 Oct;16(10):992-1003, 1-15
pubmed: 25241037
Free Radic Biol Med. 2011 Dec 1;51(11):1943-51
pubmed: 21964034
Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9585-9
pubmed: 9275166
Genes Dev. 2016 May 1;30(9):1020-33
pubmed: 27125672