Fragile histidine triad (FHIT) suppresses proliferation and promotes apoptosis in cholangiocarcinoma cells by blocking PI3K-Akt pathway.
Fragile histidine triad (FHIT) suppresses proliferation and promotes apoptosis in cholangiocarcinoma cells by blocking PI3K-Akt pathway.
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DOI：
10.1155/2014/179698
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发表时间：
2014
影响因子：
--
通讯作者：
Hu S
中科院分区：
文献类型：
--
作者：
Huang Q;Liu Z;Xie F;Liu C;Shao F;Zhu CL;Hu S
脆性组氨酸三联体(FHIT)是一种肿瘤抑制蛋白，调节癌细胞的增殖和凋亡。然而，人们对其确切的作用机制知之甚少。磷脂酰肌醇3-羟基激酶(PI3K)-Akt-Survivin是FHIT调控肺癌细胞生长的重要信号通路。为了确定FHIT对胆管癌细胞QBC939是否具有调控作用，我们构建了FHIT表达载体，并将其导入QBC939细胞。Western blotting和qRT-PCR分别检测蛋白质和mRNA的表达。用四甲基偶氮唑盐比色法和流式细胞仪检测QBC939细胞的存活率和凋亡率。结果显示，在FHIT过表达的细胞中，Survivin和Bcl2的表达下调，caspase3的表达上调。此外，FHIT还抑制Akt的磷酸化。高表达FHIT的细胞增殖和凋亡的变化明显，这与有效的肌醇磷脂3-激酶抑制剂LY294002处理的细胞相平行。LY294002可进一步降低Survivin和Bcl2的表达，升高caspase-3的水平。提示FHIT可能通过抑制Akt的磷酸化，抑制Survivin和Bcl2的表达，上调caspase3，从而阻断PI3K-Akt-Survivin通路。
Fragile histidine triad (FHIT) is a tumor suppressor protein that regulates cancer cell proliferation and apoptosis. However, its exact mechanism of action is poorly understood. Phosphatidylinositol 3-OH kinase (PI3K)-Akt-survivin is an important signaling pathway that was regulated by FHIT in lung cancer cells. To determine whether FHIT can regulate this pathway in cholangiocarcinoma QBC939 cells, we constructed an FHIT expression plasmid and used it to transfect QBC939 cells. Protein and mRNA expression were measured by western blotting and qRT-PCR, respectively. The viability and apoptosis of QBC939 cells were then assessed using MTT assays and flow cytometry. Our results revealed that the expression of survivin and Bcl-2 was downregulated, and caspase 3 was upregulated, in cells overexpressing FHIT. In addition, FHIT suppressed the phosphorylation of Akt. The changes in cell proliferation and apoptosis were obvious in cells overexpressing FHIT which parallels that of treatment with LY294002, a potent inhibitor of phosphoinositide 3-kinases. Treatment with LY294002 further decreased the expression of survivin and Bcl-2 and increased caspase-3 levels. These results suggest that FHIT can block the PI3K-Akt-survivin pathway by suppressing the phosphorylation of Akt and the expression of survivin and Bcl-2 and upregulating caspase 3.
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