Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice.
Animals
Female
Humans
Macrophage Activation
/ drug effects
Male
Mice
Mice, Transgenic
Phosphorylation
/ drug effects
Proto-Oncogene Proteins c-hck
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
Pyrroles
/ pharmacology
STAT3 Transcription Factor
/ metabolism
Stomach Neoplasms
/ drug therapy
Survival Rate
Journal
Cancer immunology research
ISSN: 2326-6074
Titre abrégé: Cancer Immunol Res
Pays: United States
ID NLM: 101614637
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
15
08
2019
revised:
08
12
2019
accepted:
24
01
2020
pubmed:
30
1
2020
medline:
11
11
2020
entrez:
30
1
2020
Statut:
ppublish
Résumé
Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.
Identifiants
pubmed: 31992566
pii: 2326-6066.CIR-19-0623
doi: 10.1158/2326-6066.CIR-19-0623
pmc: PMC8064588
mid: NIHMS1690732
doi:
Substances chimiques
Pyrimidines
0
Pyrroles
0
RK-20449
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Stat3 protein, mouse
0
HCK protein, human
EC 2.7.10.2
Hck protein, mouse
EC 2.7.10.2
Proto-Oncogene Proteins c-hck
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
428-435Subventions
Organisme : NIAID NIH HHS
ID : R01 AI113272
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
Références
Nat Rev Cancer. 2019 Feb;19(2):82-96
pubmed: 30578415
Sci Transl Med. 2013 Apr 17;5(181):181ra52
pubmed: 23596204
J Clin Invest. 2008 May;118(5):1727-38
pubmed: 18431520
Mol Cancer Ther. 2014 Feb;13(2):468-74
pubmed: 24398427
Prog Mol Biol Transl Sci. 2012;106:63-73
pubmed: 22340714
Exp Hematol. 1997 Dec;25(13):1367-77
pubmed: 9406996
Nat Med. 2005 Aug;11(8):845-52
pubmed: 16041381
Oncogene. 2014 Apr 17;33(16):2123-33
pubmed: 23644655
Cancer Cell. 2013 Aug 12;24(2):257-71
pubmed: 23948300
Mol Cell Biol. 2001 Dec;21(23):8068-81
pubmed: 11689697
Mol Cell Biol. 1987 Jun;7(6):2276-85
pubmed: 3453117
J Biol Methods. 2016 Jul 24;3(3):e49
pubmed: 31453214
Oncotarget. 2016 Aug 2;7(31):49322-49333
pubmed: 27384994
PLoS One. 2014 May 07;9(5):e95993
pubmed: 24804649
Oncotarget. 2015 Jun 30;6(18):15752-71
pubmed: 26087188
J Exp Med. 2002 Sep 2;196(5):589-604
pubmed: 12208875
Nat Rev Immunol. 2007 Jan;7(1):41-51
pubmed: 17186030
Carcinogenesis. 2009 Nov;30(11):1857-64
pubmed: 19734198
Cell. 1992 Mar 6;68(5):869-77
pubmed: 1547488
Genesis. 2017 Apr;55(4):
pubmed: 28170160
Cancer Res. 1996 Oct 15;56(20):4625-9
pubmed: 8840975
J Gastroenterol Hepatol. 2016 Jul;31(7):1257-72
pubmed: 26809278
Blood. 2010 Feb 18;115(7):1444-52
pubmed: 19897576
J Immunol. 2011 Oct 1;187(7):3806-14
pubmed: 21880978
World J Gastroenterol. 2010 Nov 14;16(42):5380-7
pubmed: 21072904
Nat Med. 2005 Dec;11(12):1314-21
pubmed: 16288283
Pathol Int. 2012 Jul;62(7):477-84
pubmed: 22691185
Neoplasia. 2005 Jun;7(6):545-55
pubmed: 16036105
Genes Dev. 1994 Feb 15;8(4):387-98
pubmed: 8125254
Cancer Cell. 2017 Apr 10;31(4):563-575.e5
pubmed: 28399411
J Biol Chem. 2014 Mar 14;289(11):7897-906
pubmed: 24482227
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Ann Oncol. 2015 May;26(5):998-1005
pubmed: 25609248