Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes.
Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes.
复制标题
Interleukin-6 可减少人类恶性胆管细胞的衰老并增加端粒酶活性。
DOI：
10.1016/j.lfs.2005.10.015
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发表时间：
2006
期刊：
影响因子：
6.1
通讯作者：
Patel,Tushar
中科院分区：
文献类型：
--
作者：
Yamagiwa,Yoko;Meng,Fanyin;Patel,Tushar
细胞衰老导致不可逆的生长停滞。在恶性细胞中，衰老是通过端粒酶活性维持染色体长度来防止的。端粒酶活性在恶性胆管细胞中升高，而在正常胆管细胞中不升高。白细胞介素-6 （IL-6）是胆管癌生长的自分泌促进因子。我们的目的是评估IL-6激活的p38丝裂原激活蛋白激酶（MAPK）途径与恶性胆管细胞衰老之间的关系。方法观察Mz-ChA-1恶性人胆管细胞的细胞衰老和端粒酶活性。评估p38 MAPK和端粒酶活性抑制剂对细胞增殖的影响，并通过中位效应分析量化这些抑制剂之间的相互作用。结果smz - cha -1细胞在重复传代过程中迅速衰老。在重复传代过程中，IL-6增加端粒酶活性，减缓细胞衰老。然而，通过抑制p38 MAPK，基底端粒酶活性增加。端粒酶活性的抑制降低了IL-6诱导的增殖，并与p38 MAPK抑制剂具有协同作用。因此，IL-6增加端粒酶活性独立于p38 MAPK信号，维持端粒酶活性促进胆管癌的生长。结论IL-6刺激下端粒酶活性的增强可防止细胞衰老，从而促进胆管癌的生长。因此，端粒酶活性的抑制可能对胆道恶性肿瘤有治疗作用。
BACKGROUND/AIMSCellular 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.METHODSCell 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.RESULTSMz-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.CONCLUSIONEnhanced 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.