Open AccessSorafenib inhibits MAPK‐mediated proliferation in a Barrett's esophageal adenocarcinoma cell line
Author(s) -
Keswani R. N.,
Chumsangsri A.,
Mustafi R.,
Delgado J.,
Cohen E. E. W.,
Bissonnette M.
Publication year - 2008
Publication title -
diseases of the esophagus
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.115
H-Index - 63
eISSN - 1442-2050
pISSN - 1120-8694
DOI - 10.1111/j.1442-2050.2007.00799.x
Subject(s) - sorafenib , mapk/erk pathway , cancer research , cyclin d1 , medicine , cell growth , bile acid , adenocarcinoma , dysplasia , cell cycle , cancer , kinase , chemistry , hepatocellular carcinoma , biochemistry
SUMMARY. Esophageal adenocarcinoma continues to rise in incidence. Despite recognition of Barrett's metaplasia as the histological precursor, prognosis remains poor. The mitogen‐activated protein kinases (MAPK) pathway is activated in Barrett's‐associated dysplasia and adenocarcinoma and this activation is, in part, due to acid and bile acid reflux. We investigated the effects of sorafenib, an orally active Raf‐inhibitor, on acid and bile acid‐stimulated growth and signaling in SEG‐1 cells, derived from a Barrett's esophageal cancer. SEG‐1 cells were pretreated with sorafenib or vehicle and subsequently stimulated with acid or bile acid. MAPK signals, including phospho‐ERK and phospho‐p38, as well as cyclin D1 expression were assessed by Western blotting. Cell proliferation was measured by WST‐1 colorimetric assay. Acid (pH 3.0–4.0) and bile acid (taurocholate 50–100 µmol/L) activated ERK and p38. Acid and bile acid exposure also increased levels of cyclin D1, a G1 to S cell cycle regulator. Furthermore, acid and taurocholate exposure increased cell proliferation. Sorafenib abrogated MAPK activation and cyclin D1 up‐regulation and significantly inhibited cell growth. In summary, sorafenib inhibits acid or bile acid‐stimulated Barrett's esophageal cancer cell proliferation by a mechanism involving the MAPK pathway. Our results suggest that sorafenib might be useful in the management of Barrett's‐associated dysplasia and adenocarcinoma. These findings provide a foundation for in vivo studies to assess the efficacy of sorafenib in Barrett's‐related neoplasia.