Authors: Lorella Bonaccorsi Sara Marchiani Monica Muratori Gianni Forti Elisabetta Baldi
Publish Date: 2004/07/16
Volume: 130, Issue: 10, Pages: 604-614
Abstract
Androgenindependent prostate cancer AIPC is characterized by a higher invasive potential compared to hormoneresponsive prostate cancer A therapeutic option for AIPC should thus be targeted to suppress not only cell proliferation but also the invasive ability of the cells Here we investigated the effect of the epidermal growth factor receptor EGFR tyrosine kinase inhibitor gefitinib ‘IRESSA’ ZD1839 on EGFstimulated invasion and proliferation in two androgenindependent prostate cancer cell lines PC3 and DU145 In addition we determined the effect of the compound on EGFstimulated PI3 K/AKT pathway activation in view of the key role exerted by this pathway in carcinoma cell invasionCell proliferation was determined by thymidine incorporation in the nuclei Cell cycle analysis was performed by flow cytometry Invasion through matrigel in vitro was measured by using Boyden chambers PI3 K activity was measured by immunokinase assay and AKT phosphorylation was evaluated by Western blot analysisGefitinib inhibits invasion through matrigel and collagen in response to EGF in both cell lines In addition we confirm the inhibitory effect of the compound on basal and EGFinduced cell proliferation Such an effect was accompanied by accumulation of the cells in the G0/G1 phase of the cell cycle The effect of the compound is due as expected to suppression of EGFinduced autotransphosphorylation of EGFR In addition we demonstrate here that gefitinib inhibits EGFinduced activation of PI3 K/AKT pathway in both cell linesOverall our results demonstrate that gefitinib is able to suppress invasion and proliferation of AIPC cells by suppressing EGFstimulated activation of the PI3 K/AKT pathway and support a possible use of the drug in the treatment of advanced PC to limit not only proliferation but also invasion to other districtsWe thank Prof Mario Maggi Endocrine Unit University of Florence and Dr Clara Crescioli Endocrine Unit University of Florence for helpful advice Supported by Associazione Italiana Ricerca sul Cancro AIRC Milan University of Florence Ministry of University and Scientific Research Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale COFIN and AstraZeneca Spa Basiglio Milan Italy
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