The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation.
A549 Cells
Adenosine Triphosphatases
/ metabolism
Autophagy
/ physiology
Cell Line, Tumor
Gene Expression
/ physiology
Glucose
/ metabolism
Glutamine
/ metabolism
Humans
MAP Kinase Signaling System
/ physiology
MCF-7 Cells
Multiple Myeloma
/ metabolism
Nuclear Proteins
/ metabolism
Nutrients
/ metabolism
PC-3 Cells
Protein Serine-Threonine Kinases
/ metabolism
Proteolysis
Proteostasis
/ physiology
Signal Transduction
/ physiology
Valosin Containing Protein
/ metabolism
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
08
05
2018
accepted:
07
12
2018
revised:
05
12
2018
pubmed:
11
1
2019
medline:
22
5
2019
entrez:
11
1
2019
Statut:
ppublish
Résumé
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.
Identifiants
pubmed: 30626938
doi: 10.1038/s41388-018-0651-z
pii: 10.1038/s41388-018-0651-z
pmc: PMC6756015
doi:
Substances chimiques
Nuclear Proteins
0
Glutamine
0RH81L854J
EIF2AK4 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Adenosine Triphosphatases
EC 3.6.1.-
p97 ATPase
EC 3.6.1.-
VCP protein, human
EC 3.6.4.6
Valosin Containing Protein
EC 3.6.4.6
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3216-3231Subventions
Organisme : Cancer Research UK
ID : 12011
Pays : United Kingdom
Organisme : Cancer Research UK (CRUK)
ID : C41494/A15448
Pays : International
Organisme : Cancer Research UK (CRUK)
ID : A22544
Pays : International
Références
Mol Cell. 2000 Nov;6(5):1099-108
pubmed: 11106749
Nature. 2001 Dec 6;414(6864):652-6
pubmed: 11740563
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):190-5
pubmed: 11756670
Nature. 2002 Jul 25;418(6896):387-91
pubmed: 12140549
Mol Cell Biol. 2002 Oct;22(19):6681-8
pubmed: 12215525
J Clin Oncol. 2003 Feb 1;21(3):447-52
pubmed: 12560433
J Clin Oncol. 2003 Jul 1;21(13):2537-44
pubmed: 12829673
J Cell Biol. 2003 Jul 7;162(1):71-84
pubmed: 12847084
Science. 1956 Jul 20;124(3212):124-5
pubmed: 13337363
Nature. 1959 Apr 25;183(4669):1201-2
pubmed: 13657053
Cell. 2003 Oct 31;115(3):355-67
pubmed: 14636562
Clin Cancer Res. 2004 May 1;10(9):3007-12
pubmed: 15131036
J Biol Chem. 2004 Aug 27;279(35):36553-61
pubmed: 15213227
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14132-8
pubmed: 16186510
Science. 2005 Dec 23;310(5756):1960-3
pubmed: 16373576
Cell. 2006 Jul 28;126(2):361-73
pubmed: 16873066
Dev Cell. 2006 Dec;11(6):803-16
pubmed: 17141156
Biochem Biophys Res Commun. 2007 Mar 9;354(2):459-65
pubmed: 17239345
Nat Cell Biol. 2007 Apr;9(4):379-90
pubmed: 17369820
J Biol Chem. 2008 Oct 31;283(44):30289-99
pubmed: 18715868
Nat Methods. 2009 Apr;6(4):275-7
pubmed: 19305406
Cancer Res. 2009 Jun 1;69(11):4918-25
pubmed: 19458066
J Biol Chem. 2009 Nov 20;284(47):32742-9
pubmed: 19783659
J Gen Physiol. 1927 Mar 7;8(6):519-30
pubmed: 19872213
Anal Chem. 2009 Dec 15;81(24):10038-48
pubmed: 19928838
Autophagy. 2010 Feb;6(2):217-27
pubmed: 20104022
Clin Cancer Res. 2010 Mar 15;16(6):1856-64
pubmed: 20215539
EMBO J. 2010 Jun 16;29(12):2082-96
pubmed: 20473272
Trends Biochem Sci. 2010 Aug;35(8):427-33
pubmed: 20570523
Mol Biol Cell. 2010 Sep 15;21(18):3220-31
pubmed: 20660158
Mol Cell. 2010 Oct 8;40(1):147-58
pubmed: 20932482
Mol Cell. 2011 Jan 7;41(1):82-92
pubmed: 21211725
Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4834-9
pubmed: 21383145
EMBO J. 1990 Jun;9(6):1757-67
pubmed: 2140770
Anal Biochem. 2011 Aug 15;415(2):206-8
pubmed: 21575589
Nat Cell Biol. 2012 Feb 02;14(2):117-23
pubmed: 22298039
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Blood. 2012 Aug 2;120(5):947-59
pubmed: 22645181
J Struct Biol. 2012 Aug;179(2):104-11
pubmed: 22735043
Mol Cell. 2012 Oct 26;48(2):242-53
pubmed: 22959274
Elife. 2013 Jan 22;2:e00308
pubmed: 23358411
Mol Cell. 2013 Mar 28;49(6):1049-59
pubmed: 23395000
Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5046-51
pubmed: 23479637
Nature. 2013 Apr 4;496(7443):101-5
pubmed: 23535601
J Cell Sci. 2013 Jul 15;126(Pt 14):3010-20
pubmed: 23687372
Cancer Lett. 2013 Aug 28;337(1):26-34
pubmed: 23726843
Nucleic Acids Res. 2013 Sep;41(16):7683-99
pubmed: 23804767
Nat Chem Biol. 2013 Sep;9(9):548-56
pubmed: 23892893
Neoplasia. 2013 Aug;15(8):989-97
pubmed: 23908598
Elife. 2014;3:e01856
pubmed: 24448410
Nature. 2014 Apr 3;508(7494):108-12
pubmed: 24670634
Biochim Biophys Acta. 2014 Sep;1843(9):1948-68
pubmed: 24732012
Cancer Cell. 2014 May 12;25(5):563-73
pubmed: 24823636
Curr Biol. 2014 Jul 21;24(14):1573-1583
pubmed: 24998528
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10586-91
pubmed: 25002487
J Cell Sci. 2014 Sep 15;127(Pt 18):3877-83
pubmed: 25146396
BMC Biol. 2014 Nov 11;12:94
pubmed: 25385277
Am J Physiol Endocrinol Metab. 2015 Feb 15;308(4):E283-93
pubmed: 25491724
Cancer Res. 2015 Feb 1;75(3):544-53
pubmed: 25644265
Sci Signal. 2015 Mar 10;8(367):ra27
pubmed: 25759478
Mol Cell. 2015 Aug 6;59(3):382-98
pubmed: 26190261
Cell Stem Cell. 2015 Nov 5;17(5):585-96
pubmed: 26440282
Genes Dev. 2015 Nov 15;29(22):2331-6
pubmed: 26543160
Cancer Cell. 2015 Nov 9;28(5):653-665
pubmed: 26555175
J Med Chem. 2015 Dec 24;58(24):9480-97
pubmed: 26565666
Cell Death Dis. 2015 Dec 31;6:e2031
pubmed: 26720340
Cell Metab. 2016 Jan 12;23(1):27-47
pubmed: 26771115
Cell Metab. 2016 Mar 8;23(3):517-28
pubmed: 26853747
Nature. 2016 Mar 24;531(7595):523-527
pubmed: 26982722
Elife. 2016 Apr 16;5:
pubmed: 27085088
Nat Cell Biol. 2016 Oct;18(10):1090-101
pubmed: 27617932
Nat Rev Cancer. 2016 Nov;16(11):680-693
pubmed: 27658530
Cell. 2017 Feb 9;168(4):657-669
pubmed: 28187287
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3565-3571
pubmed: 28320958
Mol Cancer Ther. 2017 Nov;16(11):2375-2386
pubmed: 28878026
Mol Cell. 2018 Jan 18;69(2):169-181
pubmed: 29107536
Nature. 2017 Dec 14;552(7684):194-199
pubmed: 29211715
Nature. 1988 Mar 31;332(6163):462-4
pubmed: 3352747
JAMA. 1967 Nov 27;202(9):882-8
pubmed: 5234350
Cell. 1995 Sep 22;82(6):905-14
pubmed: 7553851
Mol Cell Biol. 1995 Aug;15(8):4497-506
pubmed: 7623840
Mol Cell Biol. 1996 Aug;16(8):4273-80
pubmed: 8754828
Mol Cell Biol. 1998 Apr;18(4):2282-97
pubmed: 9528799