Proinflammatory cytokines block growth of breast cancer cells by impairing signals from a growth factor receptor.
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) -1beta 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 G(0)/G(1) 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-1beta 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.
Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, USA.
Wen-Hong
WH
Shen
Jian-Hua
JH
Zhou
Suzanne R
SR
Broussard
Gregory G
GG
Freund
Robert
R
Dantzer
Keith W
KW
Kelley
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D004273:DNA, Neoplasm; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1