Gefitinib and the modulation of the signaling pathways downstream of epidermal growth factor receptor in human liver cancer cells |
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Authors: | Jun-ichi Okano Kazuya Matsumoto Takakazu Nagahara Yoshikazu Murawaki |
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Institution: | (1) Second Department of Internal Medicine, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan |
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Abstract: | Background The transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) signaling pathway has been demonstrated to
have a pivotal role in hepatocarcinogenesis. We examined whether abrogation of the TGF-α/EGFR signaling pathway with a selective
EGFR tyrosine kinase inhibitor, gefitinib, could inhibit the proliferation of human hepatocellular carcinoma (HCC) cells.
Methods Cellular growth was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Cell-cycle distribution
was analyzed by flow cytometric analysis. Activities of signaling molecules were evaluated by Western blot analysis.
Results HCC cells expressed EGFR at variable levels; however, extracellular signal-regulated kinase (ERK)1/2 and AKT, key signaling
molecules downstream of EGFR, were not constitutively active in the cells. When HCC cells were treated with TGF-α, cellular
growth was accelerated in a manner dependent on activation of ERK1/2 and AKT. When the cells were co-treated with gefitinib
and TGF-α, enhanced proliferation and activation of ERK1/2 and AKT were canceled, and the cell-cycle promotion by TGF-α was
inhibited by co-treatment with gefitinib and TGF-α, independently of expression levels of EGFR. In contrast, gefitinib did
not show an antiproliferative effect on HCC cells cultivated under the 10% serum condition.
Conclusions The present data demonstrated that gefitinib exerted an antiproliferative action on HCC cells under a limited condition when
signaling pathways downstream of EGFR were activated by TGF-α. |
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Keywords: | gefitinib epidermal growth factor receptor signaling pathways liver cancer |
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