RRC ID 76426
Author Pan YR, Wu CE, Jung SM, Huang SC, Lin SH, Chou WC, Chang YC, Chen MH, Hung TH, Yu AL, Huang WK, Yeh CN.
Title Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.
Journal Int J Biol Sci
Abstract 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 sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.
Volume 19(9)
Pages 2772-2786
Published 2023-1-1
DOI 10.7150/ijbs.79126
PII ijbsv19p2772
PMID 37324940
PMC PMC10266071
MeSH Afatinib / therapeutic use Bile Duct Neoplasms* / pathology Bile Ducts, Intrahepatic / metabolism Cell Line, Tumor Cholangiocarcinoma* / metabolism Deoxycytidine / pharmacology Deoxycytidine / therapeutic use Drug Resistance, Neoplasm / genetics ErbB Receptors Gemcitabine Humans Mucin-4 / genetics Pancreatic Neoplasms* / pathology Proto-Oncogene Proteins c-akt
IF 4.858
Human and Animal Cells SSP-25(RCB1293)