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Carcinogenesis Advance Access published online on July 29, 2004
Carcinogenesis, doi:10.1093/carcin/bgh246
© 2004 by Oxford University Press
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Received December 19, 2003
Revised July 20, 2004
Accepted July 21, 2004

CARCINOGENESIS

IL-6 induced survival of colorectal carcinoma cells is inhibited by butyrate through downregulation of the IL-6 receptor

Hanna Yuan 1, Forrester J. Liddle 1, Sudipta Mahajan 1, David A. Frank 2

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Medicine, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115


  Abstract

Colorectal carcinoma cells are characterized by overexpression of IL-6 and the IL-6 receptor, an autocrine loop that promotes the development of many tumors. To determine the importance of this pathway, we examined the role that IL-6 plays in the biology of 228 and RKO colorectal tumor cells. IL-6 induced prominent tyrosine phosphorylation of the transcription factor STAT1 in both cell types. Furthermore, IL-6 exerts functional effects in these cells in that it inhibited apoptosis induced by Fas ligation, and upregulated Bcl-xl, a STAT target gene which can promote cell survival. Butyrate, a compound formed in the intestines of people who consume a high fiber diet, may confer protection against the development of colorectal cancer. Given the potential importance of IL-6 in the pathogenesis of colorectal tumors, we tested the hypothesis that butyrate acts by inhibiting IL-6 induced signaling events in colorectal carcinoma cells. Following treatment with butyrate, the activation of STAT1 in response to IL-6, but not interferon-{gamma}, was completely lost. Butyrate induced a prominent decrease of mRNA and cell surface expression of the IL-6 receptor {alpha} chain. Introduction of a soluble form of the IL-6R{alpha} chain restored IL-6 induced STAT1 activation and resistance to apoptosis of butyrate treated cells. These experiments indicate that IL-6 may play an important role in the pathogenesis of colorectal cancers, and that butyrate may exert its protective effect by specifically blocking IL-6 induced signaling events.


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