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

Tadahiko Shien, Hiroyoshi Doihara, Humikata Hara, Hirotoshi Takahashi, Seiji Yoshitomi, Naruto Taira, Youiti Ishibe, Jyun Teramoto, Motoi Aoe, Nobuyoshi Shimizu

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)367-373
Number of pages7
JournalBreast Cancer
Volume11
Issue number4
DOIs
Publication statusPublished - Nov 1 2004

Keywords

  • EGFR
  • EGFR-TKI
  • Gefitinib
  • Iressa
  • ZD1839

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

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