Downregulating sCLU Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Gemcitabine by Activating the Intrinsic Apoptosis Pathway
Downregulating sCLU Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Gemcitabine by Activating the Intrinsic Apoptosis Pathway
复制标题
下调sCLU通过激活内在凋亡途径增强肝细胞癌细胞对吉西他滨的敏感性
DOI：
10.1007/s10620-014-3111-9
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发表时间：
2014-08-01
影响因子：
3.1
通讯作者：
Li, Jie
中科院分区：
文献类型：
--
作者：
Xiu, Peng;Xu, Zongzhen;Li, Jie
The purpose of this study was to investigate whether the therapeutic activity of gemcitabine (GCB) in hepatocellular carcinoma (HCC) could be increased by the down-regulation of secretory clusterin (sCLU), a glycoprotein that is considered to play a cytoprotective role in the resistance to chemotherapy.The expression of sCLU was detected in HCC tumor tissues and cell lines. A cell viability and apoptosis assay were performed in parental HCC cells or the same cells transfected with sCLU shRNA and treated with or without GCB. The potential downstream pathways were investigated using the Human Apoptosis RT2 Profiler (TM) PCR Array.The expression levels of sCLU in HCC tissues were significantly higher than in adjacent non-tumor liver tissues and were associated with the histological grade and transarterial chemoembolization. sCLU overexpression was also found in three HCC cell lines and hepatocytes. The depletion of sCLU synergistically increased GCB sensitivity in Bel7402 and SMMC7721 cells and induced cell apoptosis. Based on the PCR array analysis, sCLU depletion also resulted in the up-regulation of BNIP1, GADD45A, TNFRSF10A, and TRADD and down-regulation of AKT1 in Bel7402 and SMMC7721 cells compared with the parental controls. These results were further supported by a Western blot analysis, which showed increased GADD45a protein expression and the decreased expression of phosphorylated AKT. GADD45a overexpression also increased the sensitivity to GCB in the Bel7402 and SMMC7721 cells.Targeting sCLU may be a useful method to enhance the cytotoxic effect of GCB in hepatocellular carcinoma.
