Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation

Yi Ru Pan, Chiao En Wu, Shih Ming Jung, Shih Chiang Huang, Sheng Hsuan Lin, Wen Chi Chou, Yu Chan Chang, Ming Huang Chen, Tsai Hsien Hung, Alice L. Yu, Wen Kuan Huang*, Chun Nan Yeh*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)2772-2786
Number of pages15
JournalInternational Journal of Biological Sciences
Volume19
Issue number9
DOIs
StatePublished - 2023

Bibliographical note

© The author(s).

Keywords

  • AKT inhibitor
  • GEM resistance
  • Mucin 4
  • cholangiocarcinoma
  • plasma
  • Gemcitabine
  • Humans
  • Pancreatic Neoplasms/pathology
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Mucin-4/genetics
  • Drug Resistance, Neoplasm/genetics
  • Cell Line, Tumor
  • Bile Ducts, Intrahepatic/metabolism
  • Cholangiocarcinoma/metabolism
  • Afatinib/therapeutic use
  • Bile Duct Neoplasms/pathology
  • Deoxycytidine/pharmacology

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