Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells

Hajime Isomoto, Shogo Kobayashi, Nathan W. Werneburg, Steve F. Bronk, Maria Eugenia Guicciardi, David A. Frank, Gregory J. Gores

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178 Scopus citations

Abstract

Interleukin 6 (IL-6) contributes to the pathogenesis of cholangiocarcinoma by upregulating myeloid cell leukemia-1 (Mcl-1), a key antiapoptotic Bcl-2 family member protein. IL-6 can alter gene transcription via Janus kinases (JAK) and signal transducer and activator of transcription (STAT) signal cascade. We examined this cascade in IL-6 regulation of Mcl-1 transcription in human cholangiocarcinoma cell lines. STAT3 was constitutively activated (i.e., tyrosine-phosphorylated) in cholangiocarcinoma cells but not in nonmalignant cholangiocytes. Treatment with anti-IL-6 antisera or the JAK inhibitor AG490 or transfection with dominant negative STAT3 diminished Mcl-1 messenger RNA and protein levels. Likewise, these attempts to interrupt the STAT3 cascade also reduced Mcl-1 promoter activity. Site-directed mutagenesis of a putative STAT3 consensus binding sequence decreased Mcl-1 promoter activity. Chromatin immunoprecipitation analysis demonstrated a direct binding of STAT3 to the putative STAT3 binding sequences in the Mcl-1 promoter. Downregulation of Mcl-1 by AG490 sensitized the cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. In conclusion, we have directly demonstrated a STAT3 regulatory element in the Mcl-1 promoter. Downregulation of Mcl-1 transcription by inhibiting this cascade is a potential strategy for the treatment of this cancer.

Original languageEnglish (US)
Pages (from-to)1329-1338
Number of pages10
JournalHepatology
Volume42
Issue number6
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Hepatology

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    Isomoto, H., Kobayashi, S., Werneburg, N. W., Bronk, S. F., Guicciardi, M. E., Frank, D. A., & Gores, G. J. (2005). Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology, 42(6), 1329-1338. https://doi.org/10.1002/hep.20966