Sorafenib inhibits MAPK-mediated proliferation in a Barrett's esophageal adenocarcinoma cell line

被引:21
作者
Keswani, R. N. [1 ]
Chumsangsri, A. [1 ]
Mustafi, R. [1 ]
Delgado, J. [1 ]
Cohen, E. E. W. [2 ]
Bissonnette, M. [1 ]
机构
[1] Univ Chicago, Dept Med, Gastroenterol Sect, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA
关键词
esophageal cancer; RAF inhibitor; bile acid; gastroesophageal reflux; p38;
D O I
10.1111/j.1442-2050.2007.00799.x
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 mu mol/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.
引用
收藏
页码:514 / 521
页数:8
相关论文
共 57 条
  • [11] Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial
    Bresalier, RS
    Sandler, RS
    Quan, H
    Bolognese, JA
    Oxenius, B
    Horgan, K
    Lines, C
    Riddell, R
    Morton, D
    Lanas, A
    Konstam, MA
    Baron, JA
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2005, 352 (11) : 1092 - 1102
  • [12] Mechanisms of Disease: carcinogenesis in Barrett's esophagus
    Buttar, Navtej S.
    Wang, Kenneth K.
    [J]. NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY, 2004, 1 (02): : 106 - 112
  • [13] Acid suppression therapy may not alter malignant progression in Barrett's metaplasia showing p53 protein accumulation
    Carlson, N
    Lechago, J
    Richter, J
    Sampliner, RE
    Peterson, L
    Santella, RM
    Goldblum, JR
    Falk, GW
    Ertan, A
    Younes, M
    [J]. AMERICAN JOURNAL OF GASTROENTEROLOGY, 2002, 97 (06) : 1340 - 1345
  • [14] Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci
    Cohen, Greg
    Mustafi, Reba
    Chumsangsri, Anusara
    Little, Nathaniel
    Nathanson, Jeff
    Cerda, Sonia
    Jagadeeswaran, Suiatha
    Dougherty, Urszula
    Joseph, Loren
    Hart, John
    Yerian, Lisa
    Tretiakova, Maria
    Yuan, Weihua
    Obara, Piotr
    Khare, Sharad
    Sinicrope, Frank A.
    Fichera, Alessandro
    Boss, Gerry R.
    Carroll, Robert
    Bissonnette, Marc
    [J]. CANCER RESEARCH, 2006, 66 (11) : 5656 - 5664
  • [15] Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence
    Cooper, BT
    Chapman, W
    Neumann, CS
    Gearty, JC
    [J]. ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 2006, 23 (06) : 727 - 733
  • [16] Devesa SS, 1998, CANCER, V83, P2049, DOI 10.1002/(SICI)1097-0142(19981115)83:10<2049::AID-CNCR1>3.0.CO
  • [17] 2-2
  • [18] Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett's esophagus
    不详
    [J]. AMERICAN JOURNAL OF GASTROENTEROLOGY, 2004, 99 (10) : 1865 - 1865
  • [19] Dynamic effects of acid on Barrett's esophagus - An ex vivo proliferation and differentiation model
    Fitzgerald, RC
    Omary, MB
    Triadafilopoulos, G
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (09) : 2120 - 2128
  • [20] Gibson MK, 2003, CLIN CANCER RES, V9, P6461