Proinflammatory cytokines block growth of breast cancer cells by impairing signals from a growth factor receptor

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

Research output: Contribution to journalArticlepeer-review

Abstract

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)-α at 0.1 ng/ml and is reduced by 80]% at 100 ng/ml. Similarly, both IL (interleukin)-1β 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-α significantly inhibits the antiapoptotic property of IGF-I in protecting MCF-7 cells from DNA fragmentation. TNF-α and IL-1β 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.

Original languageEnglish (US)
Pages (from-to)4746-4756
Number of pages11
JournalCancer Research
Volume62
Issue number16
StatePublished - Aug 15 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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