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Gefitinib (‘IRESSA’, ZD1839) inhibits EGF-induced invasion in prostate cancer cells by suppressing PI3 K/AKT activation

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Abstract

Purpose

Androgen-independent prostate cancer (AI-PC) is characterized by a higher invasive potential compared to hormone-responsive prostate cancer. A therapeutic option for AI-PC 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 EGF-stimulated invasion and proliferation in two androgen-independent prostate cancer cell lines PC3 and DU145. In addition, we determined the effect of the compound on EGF-stimulated PI3 K/AKT pathway activation, in view of the key role exerted by this pathway in carcinoma cell invasion.

Methods

Cell 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 analysis.

Results

Gefitinib 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 EGF-induced 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 EGF-induced autotransphosphorylation of EGFR. In addition, we demonstrate here that gefitinib inhibits EGF-induced activation of PI3 K/AKT pathway in both cell lines.

Conclusion

Overall, our results demonstrate that gefitinib is able to suppress invasion and proliferation of AI-PC cells by suppressing EGF-stimulated 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 districts.

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Fig. 1A–D
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Abbreviations

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

AI-PC:

Androgen-independent prostate cancer

PI3 K:

Phosphatidylinositol 3-kinase

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Acknowledgements

We 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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Authors and Affiliations

  1. Dept. of Clinical Physiopathology, Andrology Unit , University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Lorella Bonaccorsi, Sara Marchiani, Monica Muratori, Gianni Forti & Elisabetta Baldi

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  1. Lorella Bonaccorsi
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  2. Sara Marchiani
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  3. Monica Muratori
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  4. Gianni Forti
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  5. Elisabetta Baldi
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Correspondence to Elisabetta Baldi.

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Bonaccorsi, L., Marchiani, S., Muratori, M. et al. Gefitinib (‘IRESSA’, ZD1839) inhibits EGF-induced invasion in prostate cancer cells by suppressing PI3 K/AKT activation. J Cancer Res Clin Oncol 130, 604–614 (2004). https://doi.org/10.1007/s00432-004-0581-8

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