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

Yu-Tzu Tai, Klaus Podar, Laurence Catley, Yu-Hua Tseng, Masaharu Akiyama, Reshma Shringarpure, Renate Burger, Teru Hideshima, Dharminder Chauhan, Nicholas Mitsiades, Paul Richardson, Nikhil C Munshi, C Ronald Kahn, Constantine Mitsiades, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

189 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)5850-5858
Number of pages9
JournalCancer Research
Issue number18
Publication statusPublished - 15 Sept 2003
Externally publishedYes


  • Antibodies, Monoclonal/pharmacology
  • Cell Adhesion/drug effects
  • Cell Line, Tumor
  • Cell Movement/drug effects
  • Enzyme Activation
  • Fibronectins/metabolism
  • Humans
  • Insulin-Like Growth Factor I/antagonists & inhibitors
  • Integrin beta1/metabolism
  • Membrane Glycoproteins/metabolism
  • Membrane Microdomains/metabolism
  • Mitogen-Activated Protein Kinase 1/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases/antagonists & inhibitors
  • Multiple Myeloma/enzymology
  • Oligopeptides/pharmacology
  • Phosphatidylinositol 3-Kinases/metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • Proteoglycans/metabolism
  • Proto-Oncogene Proteins/metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor Cross-Talk/physiology
  • Receptor, IGF Type 1/metabolism
  • Signal Transduction/physiology
  • Syndecan-1
  • Syndecans


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