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J Gastroenterol. 2006 Feb;41(2):166-76.

Gefitinib and the modulation of the signaling pathways downstream of epidermal growth factor receptor in human liver cancer cells.

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  • 1Second Department of Internal Medicine, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan.

Abstract

BACKGROUND:

The transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGFR) signaling pathway has been demonstrated to have a pivotal role in hepatocarcinogenesis. We examined whether abrogation of the TGF-alpha/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-alpha, 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-alpha, enhanced proliferation and activation of ERK1/2 and AKT were canceled, and the cell-cycle promotion by TGF-alpha was inhibited by co-treatment with gefitinib and TGF-alpha, 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-alpha.

PMID:
16568376
DOI:
10.1007/s00535-005-1736-3
[PubMed - indexed for MEDLINE]
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