IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor.
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-6Ralpha) chain. Introduction of a soluble form of the IL-6Ralpha 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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Hanna
H
Yuan
Forrester J
FJ
Liddle
Sudipta
S
Mahajan
David A
DA
Frank
D002087:Butyrates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics
D002087:Butyrates; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051020:bcl-X Protein; D019000:Phosphotyrosine; D007371:Interferon-gamma