title: Insulin-like growth factor-I promotes migration in human androgen-independent prostate cancer cells via the alphavbeta3 integrin and PI3-K/Akt signaling.
abstract: In its phase of androgen-independence, prostate carcinoma is characterized by a high proliferation rate and by a strong ability to give rise to metastases. IGF-I has been shown to exert a potent mitogenic action on prostate cancer. We investigated whether IGF-I might also affect the motility of prostate cancer cells and defined the mechanism of action. We found that IGF-I promotes the migratory capacity of androgen-independent prostate cancer cells through the activation of its specific receptor, IGF-IR. This effect was accompanied by a change in cell morphology (as revealed by scanning electron microscopy), and by a rearrangement of the actin cytoskeleton. The treatment of cells with the PI3-K inhibitor, LY294002, counteracted the pro-migratory activity of IGF-I. Experiments were then performed to clarify whether the integrin, alphavbeta3, could be involved in the action of IGF-I. We demonstrated that: a) the IGF-I-induced migration of cells is completely antagonized by an antibody specifically blocking the function of alphavbeta3; b) IGF-I increases alphavbeta3 immunofluorescence at the level of cell membranes, and this effect is counteracted by LY294002; and c) IGF-I increases alphavbeta3 protein levels. Our results demonstrate that IGF-I promotes the motility of androgen-independent prostate cancer cells by modulating alphavbeta3 integrin activation/expression; these effects are mediated by the PI3-K/Akt signaling pathway. This study: a) supports a crucial role for IGF-I in the progression of the pathology towards the highly metastatic phase; and b) provides an additional rationale basis for the development of therapeutic strategies directed at the IGF-I/IGF-IR system in the treatment of androgen-independent prostate cancer.
authors.affiliation: Center for Endocrinological Oncology, Institute of Endocrinology, University of Milano, I-20133 Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Montagnani Marelli
authors.forename: Roberta M
authors.initials: RM
authors.lastname: Moretti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Procacci
authors.forename: Marcella
authors.initials: M
authors.lastname: Motta
authors.forename: Patrizia
authors.initials: P
authors.lastname: Limonta
mesh_terms: D000199:Actins / Q000378:metabolism; D000728:Androgens / Q000502:physiology; D000906:Antibodies / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D039302:Integrin alphaVbeta3 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008855:Microscopy, Electron, Scanning; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011554:Pseudopodia / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D017526:Receptor, IGF Type 1 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000199:Actins; D000728:Androgens; D000906:Antibodies; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D039302:Integrin alphaVbeta3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one