Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.
Humans
Afatinib
/ therapeutic use
Bile Duct Neoplasms
/ pathology
Bile Ducts, Intrahepatic
/ metabolism
Cell Line, Tumor
Cholangiocarcinoma
/ metabolism
Deoxycytidine
/ pharmacology
Drug Resistance, Neoplasm
/ genetics
ErbB Receptors
Gemcitabine
Mucin-4
/ genetics
Pancreatic Neoplasms
/ pathology
Proto-Oncogene Proteins c-akt
AKT inhibitor
GEM resistance
Mucin 4
cholangiocarcinoma
plasma
Journal
International journal of biological sciences
ISSN: 1449-2288
Titre abrégé: Int J Biol Sci
Pays: Australia
ID NLM: 101235568
Informations de publication
Date de publication:
2023
2023
Historique:
received:
21
09
2022
accepted:
24
04
2023
medline:
19
6
2023
pubmed:
16
6
2023
entrez:
16
6
2023
Statut:
epublish
Résumé
Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes
Identifiants
pubmed: 37324940
doi: 10.7150/ijbs.79126
pii: ijbsv19p2772
pmc: PMC10266071
doi:
Substances chimiques
Afatinib
41UD74L59M
Deoxycytidine
0W860991D6
ErbB Receptors
EC 2.7.10.1
Gemcitabine
0
Mucin-4
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
MUC4 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2772-2786Informations de copyright
© The author(s).
Déclaration de conflit d'intérêts
Competing Interests: The authors have declared that no competing interest exists.
Références
EMBO Rep. 2018 Sep;19(9):
pubmed: 29987135
Cancers (Basel). 2021 Jun 23;13(13):
pubmed: 34201707
Lancet Gastroenterol Hepatol. 2022 Jun;7(6):522-532
pubmed: 35278356
Hepatology. 2004 Jan;39(1):220-9
pubmed: 14752841
Cancer Cell. 2017 Jul 10;32(1):71-87.e7
pubmed: 28697344
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4257-64
pubmed: 16857800
Clin Cancer Res. 2022 Oct 3;28(19):4248-4257
pubmed: 35849151
Gastroenterology. 2022 Jan;162(1):253-268.e13
pubmed: 34534538
Ther Adv Med Oncol. 2012 Nov;4(6):341-6
pubmed: 23118809
World J Gastroenterol. 2011 Jun 28;17(24):2924-32
pubmed: 21734803
Biomolecules. 2021 Jan 13;11(1):
pubmed: 33451059
Biomolecules. 2020 Oct 23;10(11):
pubmed: 33113997
Carcinogenesis. 2004 Apr;25(4):631-6
pubmed: 14656942
Int J Mol Sci. 2019 Mar 14;20(6):
pubmed: 30875782
Int J Cancer. 2020 Oct 15;147(8):2190-2198
pubmed: 32359091
Nat Rev Gastroenterol Hepatol. 2013 Oct;10(10):607-20
pubmed: 23856888
Biomolecules. 2020 Sep 30;10(10):
pubmed: 33007962
Nat Rev Cancer. 2009 Dec;9(12):874-85
pubmed: 19935676
J Biol Chem. 2002 Apr 19;277(16):14040-7
pubmed: 11842081
Pharmacogenomics J. 2004;4(5):307-14
pubmed: 15224082
Mol Cancer Ther. 2014 Nov;13(11):2477-88
pubmed: 25323681
Br J Cancer. 2008 May 20;98(10):1675-81
pubmed: 18475301
Cancer Discov. 2020 Oct;10(10):1528-1543
pubmed: 32532747
Expert Opin Ther Targets. 2017 Jul;21(7):657-669
pubmed: 28460571
Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588
pubmed: 32606456
Biomolecules. 2020 Nov 09;10(11):
pubmed: 33182492
Chin Clin Oncol. 2020 Feb;9(1):2
pubmed: 32008328
JHEP Rep. 2019 Jul 10;1(4):297-311
pubmed: 32039381
Oncol Rep. 2009 Jan;21(1):49-56
pubmed: 19082442
Biochim Biophys Acta. 2014 Aug;1846(1):142-51
pubmed: 24785432
Oncogene. 2013 Mar 28;32(13):1714-23
pubmed: 22580602
Int J Biol Markers. 2000 Oct-Dec;15(4):340-2
pubmed: 11192831
Cancer Lett. 2019 Sep 10;459:30-40
pubmed: 31128213
Cancer Discov. 2017 Sep;7(9):943-962
pubmed: 28818953
Pharmacol Ther. 2017 Apr;172:101-115
pubmed: 27919797
Eur J Cancer. 2012 Jul;48(10):1558-69
pubmed: 21852110
Lancet. 2005 Oct 8;366(9493):1303-14
pubmed: 16214602
Oncol Rep. 2009 Sep;22(3):649-57
pubmed: 19639217
J Gastroenterol. 2020 Oct;55(10):944-957
pubmed: 32748173
Chang Gung Med J. 2012 Sep-Oct;35(5):420-7
pubmed: 23127347
Cancer Res. 2012 Mar 15;72(6):1557-67
pubmed: 22266220
Cancer Res. 2010 Jan 15;70(2):440-6
pubmed: 20068163
Sci Rep. 2017 Aug 11;7(1):7950
pubmed: 28801576
Ann Oncol. 2006 May;17 Suppl 5:v7-12
pubmed: 16807468
BMC Cancer. 2020 May 14;20(1):422
pubmed: 32410631
Cell Rep. 2015 Aug 11;12(6):937-43
pubmed: 26235620
J Hepatol. 1997 Dec;27(6):1057-66
pubmed: 9453432
Int J Biol Markers. 2000 Oct-Dec;15(4):330-3
pubmed: 11192829
World J Surg Oncol. 2012 Oct 27;10:224
pubmed: 23101681
Semin Liver Dis. 2004 May;24(2):115-25
pubmed: 15192785
Cancers (Basel). 2014 Sep 05;6(3):1769-92
pubmed: 25198391
Pathol Res Pract. 2010 Dec 15;206(12):805-9
pubmed: 20947262
Neoplasia. 2011 Nov;13(11):1069-80
pubmed: 22131882
Cancer Lett. 2021 Apr 10;503:91-102
pubmed: 33485947
Trends Biochem Sci. 2002 Mar;27(3):126-31
pubmed: 11893509
Pharmgenomics Pers Med. 2021 Nov 25;14:1517-1535
pubmed: 34858045
Cancer Res. 2008 Apr 1;68(7):2065-70
pubmed: 18381409
Cancer Cell. 2011 Jan 18;19(1):58-71
pubmed: 21215704