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Carcinogenesis Advance Access originally published online on July 29, 2004
Carcinogenesis 2004 25(11):2247-2255; doi:10.1093/carcin/bgh246
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Carcinogenesis vol.25 no.11 © Oxford University Press 2004; all rights reserved.

ARTICLE

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

Hanna Yuan1, Forrester J. Liddle1, Sudipta Mahajan1 and David A. Frank1,2,3

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

3 To whom correspondence should be addressed Email: david_frank{at}dfci.harvard.edu

Colorectal carcinoma cells are characterized by over-expression 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 up-regulated 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} (IL-6R{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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