title: Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3'-kinase/AKT signaling.
abstract: Insulin-like growth factor-1 (IGF-I) is a growth and survival factor in human multiple myeloma (MM) cells. Here we examine the effect of IGF-I on MM cell adhesion and migration, and define the role of beta1 integrin in these processes. IGF-I increases adhesion of MM.1S and OPM6 MM cells to fibronectin (FN) in a time- and dose-dependent manner, as a consequence of IGF-IR activation. Conversely, blocking anti-beta1 integrin monoclonal antibody, RGD peptide, and cytochalasin D inhibit IGF-I-induced cell adhesion to FN. IGF-I rapidly and transiently induces association of IGF-IR and beta1 integrin, with phosphorylation of IGF-IR, IRS-1, and p85(PI3-K). IGF-I also triggers phosphorylation of AKT and ERK significantly. Both IGF-IR and beta1 integrin colocalize to lipid rafts on the plasma membrane after IGF-I stimulation. In addition, IGF-I triggers polymerization of F-actin, induces phosphorylation of p125(FAK) and paxillin, and enhances beta1 integrin interaction with these focal adhesion proteins. Importantly, using pharmacological inhibitors of phosphatidylinositol 3'-kinase (PI3-K) (LY294002 and wortmannin) and extracellular signal-regulated kinase (PD98059), we demonstrate that IGF-I-induced MM cell adhesion to FN is achieved only when PI3-K/AKT is activated. IGF-I induces a 1.7-2.2 (MM.1S) and 2-2.5-fold (OPM6) increase in migration, whereas blocking anti-IGF-I and anti-beta1 integrin monoclonal antibodies, PI3-K inhibitors, as well as cytochalasin D abrogate IGF-I-induced MM cell transmigration. Finally, IGF-I induces adhesion of CD138+ patient MM cells. Therefore, these studies suggest a role for IGF-I in trafficking and localization of MM cells in the bone marrow microenvironment. Moreover, they define the functional association of IGF-IR and beta1 integrin in mediating MM cell homing, providing the preclinical rationale for novel treatment strategies targeting IGF-I/IGF-IR in MM.
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Laurence
authors.initials: L
authors.lastname: Catley
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akiyama
authors.forename: Reshma
authors.initials: R
authors.lastname: Shringarpure
authors.forename: Renate
authors.initials: R
authors.lastname: Burger
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D019012:Integrin beta1 / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D020239:Receptor Cross-Talk / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D053668:Syndecan-1; D053667:Syndecans
chemical_list: D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007334:Insulin-Like Growth Factor I; D019012:Integrin beta1; D008562:Membrane Glycoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D053668:Syndecan-1; D053667:Syndecans; C508241:SDC1 protein, human; C047981:arginyl-glycyl-aspartic acid; C494918:AKT1 protein, human