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[Cancer Research 62, 4746-4756, August 15, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Proinflammatory Cytokines Block Growth of Breast Cancer Cells by Impairing Signals from a Growth Factor Receptor1

Wen-Hong Shen, Jian-Hua Zhou, Suzanne R. Broussard, Gregory G. Freund, Robert Dantzer and Keith W. Kelley2

Laboratory of Immunophysiology, Department of Animal Sciences [W-H. S., J-H. Z., S. R. B., K. W. K.] and Department of Pathology, College of Medicine [G. G. F.], University of Illinois, Urbana, Illinois 61801, and Institut National de la Recherche Agronomique-Institut National de la Santé et de la Recherche Médicale U394, Unité de Recherches de Neurobiologie Intégrative, Institute François Magendie, 33077 Bordeaux, France [R. D.]

Neutralization of endogenous growth factors and administration of exogenous bioactive cytokines are two distinct biological antitumor strategies that show promise for treatment of cancer patients. In this report, we provide evidence to link both strategies as an integrative approach to cancer therapy. We tested the hypothesis that proinflammatory cytokines block growth of transformed cells by inhibiting key intracellular signaling events after activation of the insulin-like growth factor-I (IGF-I) tyrosine kinase receptor. IGF-I stimulates DNA synthesis in MCF-7 cells by 15-fold. This increase is significantly inhibited by TNF (tumor necrosis factor) -{alpha} at 0.1 ng/ml and is reduced by 80% at 100 ng/ml. Similarly, both IL (interleukin) -1ß and IL-6 significantly reduce the ability of IGF-I to promote DNA synthesis. Flow cytometry confirmed that all three of the cytokines inhibit IGF-I-induced DNA synthesis by preventing cells from entering the S phase of the cell cycle, leading to G0/G1 arrest. Although none of the cytokines alone are cytotoxic to transformed epithelial cells in the absence of serum, TNF-{alpha} significantly inhibits the antiapoptotic property of IGF-I in protecting MCF-7 cells from DNA fragmentation. TNF-{alpha} and IL-1ß act by inhibiting the IGF-I receptor from tyrosine phosphorylating insulin receptor substrate-1 without affecting tyrosine kinase activity of the IGF-IR itself. These data support the novel idea that the major inhibitory properties of proinflammatory cytokines on growth of breast cancer cells are manifested prominently in the presence of growth factors. These data also highlight growth factor receptor adaptor molecules, such as insulin receptor substrate-1, rather than the receptors themselves as targets for antitumor therapeutic strategies.




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2002 by the American Association for Cancer Research.