Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer.
Animals
Biological Transport
Cell Line, Tumor
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Glutamine
/ metabolism
Humans
Male
Metabolic Networks and Pathways
Mice
Mice, Transgenic
Mitochondria
/ metabolism
Mitochondrial Membrane Transport Proteins
/ genetics
Monocarboxylic Acid Transporters
/ metabolism
Prostatic Neoplasms
/ etiology
Prostatic Neoplasms, Castration-Resistant
/ etiology
Protein Binding
Pyruvic Acid
/ metabolism
Receptors, Androgen
/ metabolism
Signal Transduction
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
pmc-release:
01
07
2019
entrez:
15
6
2019
pubmed:
15
6
2019
medline:
15
6
2019
Statut:
ppublish
Résumé
Specific metabolic underpinnings of androgen receptor (AR)-driven growth in prostate adenocarcinoma (PCa) are largely undefined, hindering the development of strategies to leverage the metabolic dependencies of this disease when hormonal manipulations fail. Here we show that the mitochondrial pyruvate carrier (MPC), a critical metabolic conduit linking cytosolic and mitochondrial metabolism, is transcriptionally regulated by AR. Experimental MPC inhibition restricts proliferation and metabolic outputs of the citric acid cycle (TCA) including lipogenesis and oxidative phosphorylation in AR-driven PCa models. Mechanistically, metabolic disruption resulting from MPC inhibition activates the eIF2α/ATF4 integrated stress response (ISR). ISR signaling prevents cell cycle progression while coordinating salvage efforts, chiefly enhanced glutamine assimilation into the TCA, to regain metabolic homeostasis. We confirm that MPC function is operant in PCa tumors
Identifiants
pubmed: 31198906
doi: 10.1038/s42255-018-0002-y
pmc: PMC6563330
mid: NIHMS1508495
doi:
Substances chimiques
Mitochondrial Membrane Transport Proteins
0
Monocarboxylic Acid Transporters
0
Receptors, Androgen
0
Glutamine
0RH81L854J
Pyruvic Acid
8558G7RUTR
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Pagination
70-85Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NIDDK NIH HHS
ID : P01 DK113954
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA196108
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK105006
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211150
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024574
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA205257
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114356
Pays : United States
Organisme : NIA NIH HHS
ID : F30 AG050412
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167234
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220297
Pays : United States
Organisme : NIAID NIH HHS
ID : P30 AI036211
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK096093
Pays : United States
Déclaration de conflit d'intérêts
Competing Interests The authors declare no competing interests.
Références
Br J Cancer. 1999 Sep;81(2):242-51
pubmed: 10496349
Urology. 2001 Jan;57(1):108-11
pubmed: 11164153
Biochem J. 1975 Apr;148(1):85-96
pubmed: 1156402
Biochim Biophys Acta. 2005 Apr-May;1707(2-3):221-30
pubmed: 15863100
Mol Biol Cell. 2005 Dec;16(12):5493-501
pubmed: 16176978
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
J Clin Oncol. 2005 Nov 10;23(32):8253-61
pubmed: 16278481
Mol Cancer. 2006 May 15;5:17
pubmed: 16700911
Curr Protoc Cytom. 2001 May;Chapter 7:Unit 7.5
pubmed: 18770732
Cancer Res. 2009 Jan 1;69(1):16-22
pubmed: 19117982
Cell Cycle. 2009 Jan 15;8(2):268-77
pubmed: 19164938
Cancer Cell. 2010 Jul 13;18(1):11-22
pubmed: 20579941
EMBO J. 2011 May 20;30(13):2719-33
pubmed: 21602788
PLoS One. 2011;6(7):e21417
pubmed: 21789170
Cancer Res. 2011 Dec 15;71(24):7525-36
pubmed: 22007000
IUBMB Life. 2012 Jan;64(1):1-9
pubmed: 22131303
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Science. 2012 Jul 6;337(6090):93-6
pubmed: 22628554
Science. 2012 Jul 6;337(6090):96-100
pubmed: 22628558
Nat Rev Cancer. 2013 Jan;13(1):27-36
pubmed: 23192231
Clin Pharmacol Ther. 2013 Apr;93(4):352-9
pubmed: 23462886
Nat Rev Urol. 2013 Apr;10(4):219-26
pubmed: 23478540
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5422-7
pubmed: 23513224
Biochim Biophys Acta. 2013 Oct;1831(10):1518-32
pubmed: 23562839
Cancer Res. 2013 Aug 1;73(15):4599-605
pubmed: 23887973
Sci Transl Med. 2013 Aug 14;5(198):198ra108
pubmed: 23946197
Magn Reson Med. 2014 Oct;72(4):986-95
pubmed: 24186845
Clin Cancer Res. 2014 Feb 15;20(4):926-937
pubmed: 24277449
Bioinformatics. 2014 May 15;30(10):1473-5
pubmed: 24463181
Curr Alzheimer Res. 2014;11(6):564-73
pubmed: 24931567
Mol Cell. 2014 Nov 6;56(3):400-13
pubmed: 25458841
Mol Cell. 2014 Nov 6;56(3):414-24
pubmed: 25458842
Biomed Res Int. 2015;2015:845340
pubmed: 25866814
EMBO Mol Med. 2015 Sep 27;7(11):1450-64
pubmed: 26412853
Cancer Res. 2015 Nov 15;75(22):4708-17
pubmed: 26420214
Nat Genet. 2015 Nov;47(11):1346-51
pubmed: 26457646
Cell. 2015 Nov 5;163(4):1011-25
pubmed: 26544944
Urol Oncol. 2016 Aug;34(8):356-67
pubmed: 26706121
J Natl Compr Canc Netw. 2016 Jan;14(1):19-30
pubmed: 26733552
Cell Metab. 2016 Jan 12;23(1):27-47
pubmed: 26771115
Biochem J. 2016 Apr 1;473(7):929-36
pubmed: 26831515
Cell. 2016 Feb 11;164(4):681-94
pubmed: 26853473
Cell Metab. 2016 Mar 8;23(3):517-28
pubmed: 26853747
Nat Med. 2016 Mar;22(3):298-305
pubmed: 26855148
Sci Adv. 2016 May 27;2(5):e1600200
pubmed: 27386546
Cancer Metab. 2016 Aug 18;4:16
pubmed: 27540483
Nat Chem Biol. 2016 Nov;12(11):937-943
pubmed: 27618187
EMBO Rep. 2016 Oct;17(10):1374-1395
pubmed: 27629041
Nat Rev Cancer. 2016 Nov;16(11):680-693
pubmed: 27658530
Cancer Cell. 2016 Dec 12;30(6):909-924
pubmed: 27889186
Sci Transl Med. 2016 Dec 7;8(368):368ra174
pubmed: 27928028
Int J Mol Sci. 2016 Dec 10;17(12):
pubmed: 27973395
Hepatology. 2017 May;65(5):1543-1556
pubmed: 28027586
Oncotarget. 2017 Feb 7;8(6):10324-10347
pubmed: 28055971
Cell. 2017 Feb 9;168(4):657-669
pubmed: 28187287
J Cell Biol. 2017 Apr 3;216(4):1091-1105
pubmed: 28254829
Nat Cell Biol. 2017 Sep;19(9):1027-1036
pubmed: 28812582
Cell. 2017 Oct 5;171(2):358-371.e9
pubmed: 28985563
Nature. 2017 Nov 2;551(7678):115-118
pubmed: 29045397
Mol Metab. 2017 Nov;6(11):1468-1479
pubmed: 29107293
Appl Physiol Nutr Metab. 2018 May;43(5):467-474
pubmed: 29206478
Nat Med. 2018 Feb;24(2):194-202
pubmed: 29334372
Nat Commun. 2018 Mar 23;9(1):1208
pubmed: 29572438
Mol Cell. 2018 May 17;70(4):679-694.e7
pubmed: 29775582