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[Cancer Research 63, 5850-5858, September 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Insulin-like Growth Factor-1 Induces Adhesion and Migration in Human Multiple Myeloma Cells via Activation of ß1-Integrin and Phosphatidylinositol 3'-Kinase/AKT Signaling1

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 and Kenneth C. Anderson2

The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber; Cancer Institute, Boston, Massachusetts, 02115 [Y -T. T., K. P., L. C., M. A., R. S., R. B., T. H., D. C., N. M., P. R., N. C. M., C. M., K. C. A.]; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 [Y-T. T., K. P., L. C., M. A., R. S., R. B., T. H., D. C., N. M., P. R., N. C. M., C. M., K. C. A.]; and Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215 [Y-H. T., C. R. K.]

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 ß1 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-ß1 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 ß1 integrin, with phosphorylation of IGF-IR, IRS-1, and p85PI3-K. IGF-I also triggers phosphorylation of AKT and ERK significantly. Both IGF-IR and ß1 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 p125FAK and paxillin, and enhances ß1 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-ß1 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 ß1 integrin in mediating MM cell homing, providing the preclinical rationale for novel treatment strategies targeting IGF-I/IGF-IR in MM.




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