title: Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells.
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.
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Isomoto
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Werneburg
authors.forename: Steve F
authors.initials: SF
authors.lastname: Bronk
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Guicciardi
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D001665:Binding Sites; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D053613:Janus Kinase 1; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1