Insulin-like growth factor I is a dual effector of multiple myeloma cell growth.
Multiple myeloma (MM) is an invariably fatal disease that accounts for approximately 1% to 2% of all human cancers. Surprisingly little is known about the cellular pathways contributing to growth of these tumors. Although the cytokine interleukin-6 has been suggested to be the major stimulus for myeloma cell growth, the role of a second potential growth factor, insulin-like growth factor I (IGF-I), has been less clearly defined. The IGF-I signaling cascade in 8 MM cell lines was examined. In 7 of these, the IGF-I receptor (IGF-IR) was expressed and autophosphorylated in response to ligand. Downstream of IGF-IR, insulin receptor substrate 1 was phosphorylated, leading to the activation of phosphatidylinositol-3'-kinase (PI-3K). PI-3K, in turn, regulated 2 distinct pathways. The first included Akt and Bad, leading to an inhibition of apoptosis; the second included the mitogen-activated protein kinase (MAPK), resulting in proliferation. Biologic relevance of this pathway was demonstrated because in vitro IGF-I induced both an antiapoptotic and a proliferative effect. Importantly, in vivo administration of IGF-I in SCID mice inoculated with the OPM-2 line led to approximately twice the growth rate of tumor cells as in controls. These results suggest that IGF-I activates at least 2 pathways effecting myeloma cell growth and contributes significantly to expansion of these cells in vivo. (Blood. 2000;96:2856-2861)
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Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Rudikoff
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000637:transplantation; D051025:bcl-Associated Death Protein
D002352:Carrier Proteins; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C494820:Bad protein, mouse; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C494918:AKT1 protein, human