Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer.
Activating Transcription Factor 4
/ metabolism
Adenocarcinoma
/ genetics
Animals
Biomarkers, Tumor
/ metabolism
Carcinoma, Pancreatic Ductal
/ genetics
Cell Line, Tumor
Cell Movement
Cell Survival
Epithelial-Mesenchymal Transition
Gene Expression Regulation, Neoplastic
Glutamine
/ metabolism
HEK293 Cells
Humans
MAP Kinase Signaling System
Mice, Inbred C57BL
Neoplasm Metastasis
Pancreatic Neoplasms
/ genetics
RNA, Messenger
/ genetics
Snail Family Transcription Factors
/ genetics
Stress, Physiological
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 09 2020
07 09 2020
Historique:
received:
02
03
2020
revised:
10
04
2020
accepted:
06
05
2020
entrez:
9
6
2020
pubmed:
9
6
2020
medline:
3
3
2021
Statut:
ppublish
Résumé
Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the up-regulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility, and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.
Identifiants
pubmed: 32510550
pii: 151843
doi: 10.1084/jem.20200388
pmc: PMC7478719
pii:
doi:
Substances chimiques
ATF4 protein, human
0
Biomarkers, Tumor
0
RNA, Messenger
0
Snail Family Transcription Factors
0
Glutamine
0RH81L854J
Activating Transcription Factor 4
145891-90-3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200643
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207189
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA211036
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 Recouvreux et al.
Déclaration de conflit d'intérêts
Disclosures: A. Lowy reported personal fees from Merck, personal fees from Rafael, and grants from Syros outside the submitted work. No other disclosures were reported.
Références
Cold Spring Harb Protoc. 2016 Sep 01;2016(9):
pubmed: 27587774
EMBO J. 2010 Jun 16;29(12):2082-96
pubmed: 20473272
Nat Commun. 2017 Jul 03;8:15965
pubmed: 28671190
Nat Cell Biol. 2016 Oct;18(10):1090-101
pubmed: 27617932
Cancer Res. 2009 Dec 15;69(24):9228-35
pubmed: 19920183
Nat Cell Biol. 2017 May;19(5):518-529
pubmed: 28414315
Cell Metab. 2019 Feb 5;29(2):254-267
pubmed: 30581118
Nat Rev Cancer. 2013 Feb;13(2):97-110
pubmed: 23344542
Nat Med. 2011 Apr;17(4):500-3
pubmed: 21460848
J Exp Clin Cancer Res. 2012 Aug 27;31:68
pubmed: 22925330
PLoS One. 2009;4(3):e4715
pubmed: 19262748
Trends Cancer. 2017 Mar;3(3):169-180
pubmed: 28393116
Genes Dev. 2004 May 15;18(10):1131-43
pubmed: 15155580
Br J Cancer. 2011 Jul 26;105(3):393-402
pubmed: 21750550
J Biol Chem. 2008 Apr 18;283(16):10848-57
pubmed: 18287093
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cancer Cell. 2005 May;7(5):469-83
pubmed: 15894267
Gastroenterology. 2018 Dec;155(6):1999-2013.e3
pubmed: 30165049
Oncotarget. 2015 Apr 10;6(10):7379-89
pubmed: 25749035
Nat Cell Biol. 2019 Dec;21(12):1590-1603
pubmed: 31740775
Cancer Cell. 2018 Jan 8;33(1):91-107.e6
pubmed: 29316436
Oncotarget. 2016 May 3;7(18):25251-63
pubmed: 26958807
Dev Cell. 2019 May 6;49(3):361-374
pubmed: 31063755
EMBO Rep. 2016 Oct;17(10):1374-1395
pubmed: 27629041
Nature. 2015 Nov 26;527(7579):525-530
pubmed: 26560028
Cancer Cell. 2012 Jun 12;21(6):822-35
pubmed: 22698406
Mol Cell. 2014 Oct 23;56(2):205-218
pubmed: 25242145
Nature. 2016 Mar 3;531(7592):47-52
pubmed: 26909576
Elife. 2013 May 28;2:e00498
pubmed: 23741617
FEBS J. 2017 Oct;284(19):3132-3144
pubmed: 28444969
Dev Cell. 2018 Jun 18;45(6):681-695.e4
pubmed: 29920274
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
Cell. 2005 Nov 18;123(4):641-53
pubmed: 16286009
Nat Rev Mol Cell Biol. 2014 Mar;15(3):178-96
pubmed: 24556840
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Hepatogastroenterology. 2008 Nov-Dec;55(88):2016-27
pubmed: 19260470
Carcinogenesis. 2005 Mar;26(3):513-23
pubmed: 15358632
Mol Oncol. 2015 Apr;9(4):758-71
pubmed: 25579086
Genes Dev. 2017 Jan 1;31(1):18-33
pubmed: 28096186
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cell Metab. 2018 Nov 6;28(5):721-736.e6
pubmed: 30122553
Oncotarget. 2017 Jun 21;8(32):53154-53167
pubmed: 28881801
Dev Cell. 2016 Mar 7;36(5):540-9
pubmed: 26954548
Nature. 2017 Nov 2;551(7678):115-118
pubmed: 29045397
Cell. 2012 Jan 20;148(1-2):349-61
pubmed: 22265420
Nature. 2013 Apr 4;496(7443):101-5
pubmed: 23535601
Clin Cancer Res. 2007 Aug 15;13(16):4769-76
pubmed: 17699854
Nat Commun. 2019 Apr 3;10(1):1523
pubmed: 30944313
Mol Cancer Ther. 2018 Sep;17(9):1824-1832
pubmed: 30181331
Stem Cells. 2009 Sep;27(9):2059-68
pubmed: 19544473
Cell. 2016 Jun 30;166(1):21-45
pubmed: 27368099
Nature. 2017 Jul 5;547(7661):E7-E8
pubmed: 28682339
J Cell Sci. 2019 Dec 2;132(23):
pubmed: 31792043
Dev Cell. 2019 Aug 5;50(3):381-392.e5
pubmed: 31257175
PLoS One. 2012;7(5):e36510
pubmed: 22570721
Cancer Res. 2015 Feb 1;75(3):544-53
pubmed: 25644265