Bile salt exposure increases proliferation through p38 and ERK MAPK pathways in a non-neoplastic Barrett's cell line

Kshama Jaiswal, Christie Lopez-Guzman, Rhonda F. Souza, Stuart J. Spechler, George A. Sarosi

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Abstract

Bile reflux has been implicated in the neoplastic progression of Barrett's esophagus (BE). Bile salts increase proliferation in a Barrett's-associated adenocarcinoma cell line (SEG-1 cells) by activating ERK and p38 MAPK pathways. However, it is not clear that these findings in cancer cells are applicable to non-neoplastic cells of benign BE. We examined the effect of bile salts on three human cell lines: normal esophageal squamous (NES) cells, non-neoplastic Barrett's cells (BAR cells), and SEG-1 cells. We hypothesized that bile salt exposure activates proproliferative and antiapoptotic pathways to promote increased growth in BE. NES, BAR, and SEG-1 cells were exposed to glycochenodeoxycholic acid (GCDA) at a neutral pH for 5 min. Proliferation was measured by Coulter counter cell counts and a 5-bromo-2′-deoxyuridine (BrdU) incorporation assay. GCDA-induced MAPK activation was examined by Western blot analysis for phosphorylated ERK and p38. Apoptosis was measured by TdT-mediated dUTP nick-end labeling and annexin V staining after GCDA and UV-B exposure. Statistical significance was determined by ANOVA. NES cells exposed to 5 min of GCDA did not increase cell number. In BAR cells, GCDA exposure increased cell number by 31%, increased phosphorylated p38 and ERK levels by two- to three-fold, increased BrdU incorporation by 30%, and decreased UV-induced apoptosis by 15-20%. In conclusion, in a non-neoplastic Barrett's cell line, GCDA exposure induces proliferation by activation of both ERK and p38 MAPK pathways. These findings suggest a potential mechanism whereby bile reflux may facilitate the neoplastic progression of BE.

Original languageEnglish (US)
Pages (from-to)G335-G342
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume290
Issue number2
DOIs
StatePublished - Feb 1 2006

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Keywords

  • Bile salts
  • Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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