Activation of insulin-like growth factor I receptor signaling pathway is critical for mouse plasma cell tumor growth.
Plasma cell neoplasia in humans generally occurs as multiple myeloma, an incurable form of cancer. Tumors with marked similarity can be induced in mice by a variety of agents, including chemicals, silicone, and oncogene-containing retroviruses, suggesting the use of murine tumors as an informative model to study plasma cell disease. Herein, we have focused on the role of insulin-like growth factor I receptor (IGF-IR) signaling in the development of plasma cell disease. The insulin receptor substrate 2/phosphatidylinositol 3'-kinase/p70S6K pathway was found to be either constitutively or IGF-I-dependently activated in all plasma cell tumors. Biological relevance was demonstrated in that plasma cell lines with up-regulated IGF-IR expression levels exhibited mitogenic responses to IGF-I. More importantly, expression of a dominant-negative mutant of IGF-IR in these lines strongly suppressed tumorigenesis in vivo. Taken together, these results demonstrate that up-regulation and activation of IGF-IR and the downstream signaling pathway involving insulin receptor substrate 2, phosphatidylinositol 3'-kinase, and p70S6K may play an important role in the development of a broad spectrum of plasma cell tumors.
Department of Oncology/Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA. wwl@gunet.georgetown.edu
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W
Li
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Hyun
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M
Heller
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Yam
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Flechner
J H
JH
Pierce
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S
Rudikoff
D000818:Animals; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D005260:Female; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016393:Lymphoma, B-Cell / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010954:Plasmacytoma / Q000139:chemically induced / Q000378:metabolism*; D011233:Precipitin Tests; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism* / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D016895:Culture Media, Serum-Free; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D016315:Proto-Oncogene Proteins c-abl; D019908:Proto-Oncogene Proteins c-raf; D019893:Ribosomal Protein S6 Kinases