Premium
Cimetidine inhibits epidermal growth factor‐induced cell signaling
Author(s) -
Fujikawa Tatsuya,
Shiraha Hidenori,
Nakanishi Yutaka,
Takaoka Nobuyuki,
Ueda Naoki,
Suzuki Mayumi,
Shiratori Yasushi
Publication year - 2007
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2006.04541.x
Subject(s) - autophosphorylation , cimetidine , cell growth , epidermal growth factor , intracellular , cell culture , medicine , cancer research , microbiology and biotechnology , endocrinology , biology , receptor , kinase , protein kinase a , biochemistry , genetics
Background: Cimetidine, a histamine‐2 (H 2 ) receptor antagonist, has been demonstrated to have anticancer effects on colorectal cancer, melanoma and renal cell carcinoma. In the current study, we clarified that cimetidine inhibits both epidermal growth factor (EGF)‐induced cell proliferation and migration in hepatocellular carcinoma (HCC) cell lines. Method: HCC cell lines (Hep3B, HLF, SK‐Hep‐1, JHH‐2, PLC/PRF/5 and HLE) were used and cell proliferation was assessed by [ 3 H]‐thymidine incorporation assay. Cell migration was measured by in vitro cell migration assay. Biological effects of cimetidine were assessed with human EGF receptor (EGFR)‐expressing mouse fibroblast cells (NR6‐WT). The autophosphorylation of EGFR and the activation of other downstream effectors were analyzed by immunoprecipitation and immunoblotting. The concentration of intracellular cyclic AMP (cAMP) was measured by competitive enzyme immunoassay. Results: Cimetidine inhibited both EGF‐induced cell proliferation and migration in Hep3B, HLF, SK‐Hep‐1 and JHH‐2, while cimetidine did not affect EGF‐induced cell proliferation and migration in PLC/PRF/5 and HLE. Cimetidine was revealed to disrupt the EGF‐induced autophosphorylation of EGFR and its downstream effectors, mitogen activated protein kinases and phospholipase C‐γ. To define the molecular basis of this negative regulation, we identified that cimetidine significantly decreased intracellular cAMP levels and that decrement of cAMP inhibited autophosphorylation of EGFR. The cell permeable cAMP analog, CPT‐cAMPS reversed the cimetidine‐induced inhibition of EGF‐induced cell proliferation and cell migration by restoring autophosphorylation of EGFR. Conclusion: Cimetidine inhibited EGF‐induced cell proliferation and migration in HCC cell lines by decreasing the concentration of intracellular cAMP levels. Cimetidine may be a candidate chemopreventive agent for HCC.