Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells

Jung Hwan Yoon, Geum Youn Gwak, Hyo Suk Lee, Steven F. Bronk, Nathan W. Werneburg, Gregory J. Gores

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

Epidermal growth factor receptor (EGFR) signaling has been implicated in the genesis and progression of cholangiocarcinoma. However, the characteristics of EGFR signaling in cholangiocarcinoma cells have not been characterized. Thus, we attempted to more fully characterize EGF/EGFR signaling in human cholangiocarcinoma cells. EGFR phosphorylation and ubiquitination were evaluated using immunoblot techniques. EGFR internalization was analyzed by immunofluorescent staining of EGFR or by immunoblot analysis for biotinylated EGFR. Cell growth was assessed using the MTS assay. EGFR activation was sustained following EGF stimulation in cholangiocarcinoma cells as compared to hepatoma cells. This prolonged EGFR activation resulted in extended p42/44 MAPK activation in cholangiocarcinoma cells. Despite ubiquitination, EGFR activation-dependent internalization was defective in cholangiocarcinoma cells. Cell growth was increased in cholangiocarcinoma cells following EGF stimulation as compared to hepatoma cells, and this was significantly attenuated by EGFR kinase inhibitors. The EGFR kinase inhibitors also significantly decreased COX-2 expression in cholangiocarcinoma cells, while this was not evident in hepatoma cells. The results demonstrate that cholangiocarcinoma cells exhibit sustained EGFR activation due to defective receptor internalization. As EGFR kinase inhibitors effectively attenuated cellular growth, these agents may be therapeutically efficacious in human cholangiocarcinoma.

Original languageEnglish (US)
Pages (from-to)808-814
Number of pages7
JournalJournal of hepatology
Volume41
Issue number5
DOIs
StatePublished - Nov 2004

Keywords

  • Cholangiocarcinoma
  • Kinase inhibitor
  • Tyrosine kinases

ASJC Scopus subject areas

  • Hepatology

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