Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes.
OBJECTIVE
Cellular senescence results in irreversible growth arrest. In malignant cells, senescence is prevented by maintenance of chromosomal length by telomerase activity. Telomerase activity is increased in malignant, but not in normal cholangiocytes. Interleukin-6 (IL-6) is an autocrine promoter of cholangiocarcinoma growth. Our aims were to assess the relationship between IL-6 activated p38 mitogen-activated protein kinase (MAPK) pathways and senescence in malignant cholangiocytes.


METHODS
Cell senescence and telomerase activity was assessed in Mz-ChA-1 malignant human cholangiocytes. The effect of inhibitors of p38 MAPK and telomerase activity on cell proliferation was assessed, and the interaction between these inhibitors was quantitated by median effects analysis.


RESULTS
Mz-ChA-1 cells rapidly underwent senescence during repeated passaging. IL-6 increased telomerase activity and decreased cellular senescence during repeated passaging. However, basal telomerase activity was increased by inhibition of p38 MAPK. Inhibition of telomerase activity decreased IL-6 induced proliferation and had a synergistic effect with p38 MAPK inhibitors. Thus, IL-6 increases telomerase activity independent of p38 MAPK signaling and maintenance of telomerase activity promotes cholangiocarcinoma growth.


CONCLUSIONS
Enhanced telomerase activity in response to IL-6 stimulation can prevent cellular senescence and thereby contribute to cholangiocarcinoma growth. Inhibition of telomerase activity may therefore be therapeutically useful in biliary tract malignancies.
Yamagiwa
Yoko
Y
Scott & White Clinic, Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76508, USA.
Meng
Fanyin
F
Patel
Tushar
T
D001652:Bile Ducts / Q000166:cytology* / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004347:Drug Interactions; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008934:Mitogens / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007093:Imidazoles; D015850:Interleukin-6; D008934:Mitogens; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D019098:Telomerase; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole