Journal
HEPATOLOGY
Volume 42, Issue 6, Pages 1329-1338Publisher
WILEY
DOI: 10.1002/hep.20966
Keywords
-
Categories
Funding
- NIDDK NIH HHS [DK-59427] Funding Source: Medline
Ask authors/readers for more resources
Interleukin 6 (IL-6) contributes to the pathogenesis of cholangiocarcinoma by upregulating myeloid cell leukemia- 1 (Mcl-1), a key antiapoptotic Bd-2 family member protein. IL-6 can after gene transcription via Janus kinases UAK) 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. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/uppmat/index.html).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available