Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma.
Animals
Esophageal Neoplasms
/ enzymology
Esophageal Squamous Cell Carcinoma
/ enzymology
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Mice
Neoplasm Proteins
/ biosynthesis
Radiation Tolerance
Ribosomal Protein S6 Kinases, 90-kDa
/ biosynthesis
Signal Transduction
Transcription Factors
/ genetics
Tumor Suppressor Proteins
/ genetics
Xenograft Model Antitumor Assays
Cancer
Oncology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
03 08 2020
03 08 2020
Historique:
received:
11
11
2019
accepted:
06
05
2020
pubmed:
13
5
2020
medline:
3
2
2021
entrez:
13
5
2020
Statut:
ppublish
Résumé
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the β-catenin signaling pathway through direct phosphorylation of GSK-3β at Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improved radiosensitivity in both nude mouse and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α/RSK4/GSK-3β axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.
Identifiants
pubmed: 32396532
pii: 134930
doi: 10.1172/JCI134930
pmc: PMC7410060
doi:
pii:
Substances chimiques
Neoplasm Proteins
0
TP63 protein, human
0
Transcription Factors
0
Tumor Suppressor Proteins
0
RPS6KA6 protein, human
EC 2.7.11.1
Ribosomal Protein S6 Kinases, 90-kDa
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4301-4319Références
Sci Signal. 2015 Jul 28;8(387):re9
pubmed: 26221054
Br J Cancer. 2013 Sep 3;109(5):1137-46
pubmed: 23942078
Biochem Biophys Res Commun. 2013 Oct 11;440(1):112-8
pubmed: 24055036
Gastroenterology. 2018 Jan;154(2):360-373
pubmed: 28823862
J Biol Chem. 2005 Apr 8;280(14):13304-14
pubmed: 15632195
Am J Clin Nutr. 1976 Jan;29(1):105-9
pubmed: 2006
Int J Cancer. 2010 Nov 1;127(9):2051-62
pubmed: 20127860
Hum Pathol. 2005 Feb;36(2):187-94
pubmed: 15754296
BMC Genomics. 2010 Oct 18;11:576
pubmed: 20955586
Science. 1999 Mar 26;283(5410):2089-91
pubmed: 10092233
Anticancer Res. 2016 Mar;36(3):1267-74
pubmed: 26977024
J Immunol Methods. 2009 Aug 15;347(1-2):70-8
pubmed: 19567251
Cancer Cell. 2017 Jan 9;31(1):35-49
pubmed: 28041841
Oncogene. 2007 Feb 1;26(5):683-700
pubmed: 16878154
J Thorac Oncol. 2014 Sep;9(9):1398-405
pubmed: 25122435
Nature. 2017 Jan 12;541(7636):169-175
pubmed: 28052061
Clin Cancer Res. 2011 Apr 15;17(8):2120-9
pubmed: 21372219
Cancer Biol Med. 2017 Feb;14(1):33-41
pubmed: 28443201
EMBO J. 1997 Jul 1;16(13):3797-804
pubmed: 9233789
Semin Cancer Biol. 2017 Jun;44:60-66
pubmed: 28366541
Clin Cancer Res. 2016 Feb 1;22(3):691-703
pubmed: 26405196
Clin Cancer Res. 2008 Jul 15;14(14):4427-36
pubmed: 18628456
Pediatr Blood Cancer. 2014 Jan;61(1):107-15
pubmed: 23940083
Nature. 2009 Oct 22;461(7267):1071-8
pubmed: 19847258
PLoS One. 2011 Apr 21;6(4):e18196
pubmed: 21533028
Nat Rev Cancer. 2015 May;15(5):311-6
pubmed: 25907221
Mol Cancer Res. 2007 Feb;5(2):171-81
pubmed: 17314274
Biochem J. 2012 Jan 15;441(2):553-69
pubmed: 22187936
Trends Cancer. 2017 Apr;3(4):302-312
pubmed: 28718440
Cell Mol Biol Lett. 2011 Jun;16(2):296-327
pubmed: 21442444
CA Cancer J Clin. 2016 Mar-Apr;66(2):115-32
pubmed: 26808342
Mod Pathol. 2014 May;27(5):775-83
pubmed: 24201124
BMC Genomics. 2015 Aug 07;16:584
pubmed: 26251276
Oncogene. 2013 Apr 4;32(14):1794-810
pubmed: 22614021
Biochem J. 2007 Jan 1;401(1):29-38
pubmed: 17040210
Dev Biol. 2006 Jan 1;289(1):253-61
pubmed: 16324689
Nat Rev Cancer. 2013 Feb;13(2):136-43
pubmed: 23344544
Crit Rev Oncol Hematol. 2015 Oct;96(1):9-19
pubmed: 25913844
Genomics. 1999 Dec 15;62(3):332-43
pubmed: 10644430
J Clin Invest. 2010 Apr;120(4):1165-77
pubmed: 20234090
Cell J. 2016 Jul-Sep;18(2):159-64
pubmed: 27540520
J Thorac Dis. 2017 Mar;9(3):849-859
pubmed: 28449496
Histopathology. 2015 Sep;67(3):368-77
pubmed: 25641082
EMBO J. 2019 Sep 16;38(18):e101801
pubmed: 31393028
Cell Stem Cell. 2015 Mar 5;16(3):225-38
pubmed: 25748930
Curr Opin Cell Biol. 2007 Apr;19(2):150-8
pubmed: 17306971
Clin Cancer Res. 2001 Mar;7(3):469-72
pubmed: 11297235
Nat Cell Biol. 2004 Oct;6(10):931-40
pubmed: 15448698
J Clin Invest. 2013 Jun;123(6):2551-63
pubmed: 23635776
Int J Cancer. 2012 Jul 15;131(2):E45-55
pubmed: 22020623
Cell Stem Cell. 2014 Mar 6;14(3):275-91
pubmed: 24607403
EBioMedicine. 2015 Nov 19;2(12):1944-56
pubmed: 26844273
Clin Cancer Res. 2011 May 1;17(9):2955-66
pubmed: 21385931
Med Oncol. 2016 Feb;33(2):11
pubmed: 26732474
Mol Cell Biol. 2007 Jun;27(11):4006-17
pubmed: 17387146
Cancer Cell. 2002 May;1(4):369-79
pubmed: 12086851
Stem Cell Reports. 2016 Oct 11;7(4):787-801
pubmed: 27618721
Nat Commun. 2015 Jul 09;6:7679
pubmed: 26158630
Cancer Sci. 2016 Oct;107(10):1363-1372
pubmed: 27486911
Cancer Res. 2006 Aug 1;66(15):7589-97
pubmed: 16885358
Am J Physiol Cell Physiol. 2004 Jul;287(1):C171-81
pubmed: 15189821
Adv Drug Deliv Rev. 2017 Jan 15;109:63-73
pubmed: 26877102
Nat Rev Mol Cell Biol. 2008 Oct;9(10):747-58
pubmed: 18813292
N Engl J Med. 2012 May 31;366(22):2074-84
pubmed: 22646630
Nat Med. 2006 Jan;12(1):89-98
pubmed: 16341242