title: Signaling mechanisms that mediate invasion in prostate cancer cells.
abstract: Recent evidence indicates that androgen-sensitive prostate cancer cells have a less malignant phenotype characterized by reduced migration and invasion. We investigated whether the presence of the androgen receptor could affect EGFR-mediated signaling by evaluating autotransphosphorylation of the receptor as well as activation of the downstream signaling pathway PI3K/AKT. Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells. In addition, EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881, indicating decreased functionality of EGFR. Our results suggest that the expression of androgen receptors by transfection in PC3 cells confers a less malignant phenotype by interfering with EGFR autophosphorylation and signaling leading to invasion in response to EGF. We used the selective tyrosine kinase inhibitor of the EGFR gefitinib (also known as Iressa or ZD1839) to further investigate the role of EGFR in the invasion and growth of PC cells. We demonstrate that in the androgen-insensitive cell lines PC3 and DU145 this compound was able to decrease in vitro invasion of Matrigel by inhibiting EGFR autotransphosphorylation and subsequent PI3K activation. Gefitinib may be useful in the treatment of androgen-independent prostate cancer to limit not only the proliferation but also the invasion of these tumors.
authors.affiliation: Dipartimento di Fisiopatologia Clinica (Unità di Andrologia), University of Florence, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bonaccorsi
authors.forename: S
authors.initials: S
authors.lastname: Marchiani
authors.forename: M
authors.initials: M
authors.lastname: Muratori
authors.forename: V
authors.initials: V
authors.lastname: Carloni
authors.forename: G
authors.initials: G
authors.lastname: Forti
authors.forename: E
authors.initials: E
authors.lastname: Baldi
mesh_terms: D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D007797:Laminin / Q000737:chemistry; D008297:Male; D009361:Neoplasm Invasiveness; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011509:Proteoglycans / Q000737:chemistry; D011799:Quinazolines / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
chemical_list: D000728:Androgens; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D011509:Proteoglycans; D011799:Quinazolines; D011944:Receptors, Androgen; C059485:matrigel; D014443:Tyrosine; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077156:Gefitinib