title: Gefitinib ('IRESSA', ZD1839) inhibits EGF-induced invasion in prostate cancer cells by suppressing PI3 K/AKT activation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dept. of Clinical Physiopathology, Andrology Unit, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Bonaccorsi
authors.forename: Sara
authors.initials: S
authors.lastname: Marchiani
authors.forename: Monica
authors.initials: M
authors.lastname: Muratori
authors.forename: Gianni
authors.initials: G
authors.lastname: Forti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Baldi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; C494918:AKT1 protein, human