Sorafenib inhibits MAPK-mediated proliferation in a Barrett's esophageal adenocarcinoma cell line.
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 micromol/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.
Keswani
R N
RN
Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, Illinois, USA.
Chumsangsri
A
A
Mustafi
R
R
Delgado
J
J
Cohen
E E W
EE
Bissonnette
M
M
D000230:Adenocarcinoma / Q000473:pathology; D000704:Analysis of Variance; D001471:Barrett Esophagus / Q000473:pathology; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000473:pathology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011336:Probability; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012016:Reference Values; D000077157:Sorafenib
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D020928:Mitogen-Activated Protein Kinases