PLC and PI3K pathways are important in the inhibition of EGF-induced cell migration by gefitinib ('Iressa', ZD1839)

被引：25

作者：

Shien T. ^{[1
]}

Doihara H. ^{[1
]}

Hara H. ^{[1
]}

Takahashi H. ^{[1
]}

Yoshitomi S. ^{[1
]}

Taira N. ^{[1
]}

Ishibe Y. ^{[1
]}

Teramoto J. ^{[1
]}

Aoe M. ^{[1
]}

Shimizu N. ^{[1
]}

机构：

[1] Department of Surgery II, University of Okayama, 700-8558, Okayama

来源：

Breast Cancer | 2004年 / 11卷 / 4期

关键词：

EGFR; EGFR-TKI; Gefitinib; Iressa; ZD1839;

D O I：

10.1007/BF02968044

中图分类号：

学科分类号：

摘要：

Background: Expression of epidermal growth factor receptor (EGFR) by human breast cancer tissues is associated with poor clinical response. The EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839), is a leading example of a molecular targeted agent, and has an anti-proliferative effect on various cancer cells. But the details of the anti-cancer effect and mechanism have not been elucidated. We studied the anti-cancer effect of gefitinib in breast cancer cell lines and the intracellular pathway downstream of EGFR associated with cell migration. Methods: In this study, we analysed the anti-proliferative and anti-migratory effect of gefitinib in EGFR (+) breast cancer cell lines by WST-1 analysis and chemotaxis chamber analysis. We analyzed several intracellular phosphorylated pathways which are activated by mitogen activated kinases (extracellular signal-regulated protein kinase 1 and 2: MEK), phosphatidylinositol 3'-kinase (PI3K) and phpspholipase C (PLC), by blocking those pathways using inhibitors of each kinase, and also investigated the effects on the phosphorylation of myosin light chain (MLC). Results: Gefitinib inhibited proliferation in most of these cell lines. MDA-MB231 was shown to be resistant. Furthermore, proliferation of MDA-MB231 cells was not affected by EGF stimulation, but migration of MDA-MB231 cells was significantly inhibited. PI3K and PLC inhibitors blocked EGF-stimulated cell migration and MLC phosphorylation, but the MEK inhibitor did not influence cell migration. Conclusions: Gefitinib has an anti-migratory effect on MDA-MB231 that results in an anti-proliferative effect. PI3K and PLC are important for the migration of MDA-MB231 cells, and gefitinib may inhibit migration by blocking these signalling pathways.

引用

页码：367 / 373

页数：6

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