The tyrosine kinase inhibitor sorafenib sensitizes hepatocellular carcinoma cells to taxol by suppressing the HURP protein
The tyrosine kinase inhibitor sorafenib sensitizes hepatocellular carcinoma cells to taxol by suppressing the HURP protein
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DOI：
10.1016/j.bcp.2011.04.008
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发表时间：
2011-07-15
影响因子：
5.8
通讯作者：
Chao, Chuck C. -K.
中科院分区：
文献类型：
--
作者：
Kuo, Tzu-Ching;Lu, Hsing-Pang;Chao, Chuck C. -K.
肝癌上调蛋白（HURP）代表了一种推定的癌基因，在许多人类癌症，特别是肝细胞癌（HCC）中过表达。HURP在有丝分裂纺锤体形成过程中起着重要作用，这是一个被各种抗癌药物如紫杉醇靶向的过程。然而，HURP在肝癌紫杉醇耐药形成过程中的作用尚不清楚。在本研究中，我们观察到肝癌细胞中高水平的HURP蛋白与紫杉醇耐药相关。HURP敲除后，肝癌细胞对紫杉醇治疗表现出更敏感的反应。值得注意的是，索拉非尼，一种被批准用于治疗HCC的酪氨酸激酶抑制剂，主要在转录水平抑制HURP表达，并使HCC细胞对亚致死剂量的紫杉醇敏感。通过使用实时PCR和染色质免疫沉淀分析，我们观察到NF-κ B B家族成员c-Rel代表一个假定的激活HURP基因表达的转录因子。此外，索拉非尼对HURP表达的抑制作用归因于c-Rel的翻译和核转位减少。因此，使用短发夹RNA下调c-Rel显示出降低HURP蛋白水平并增强紫杉醇诱导的细胞死亡。总之，我们的研究结果表明，HURP作为一种新的生存蛋白，保护肝癌细胞免受紫杉醇诱导的细胞死亡。此外，NF-κ B信号对HURP基因表达的调节似乎是肝癌细胞对紫杉醇反应的关键。(C)2011 Elsevier Inc. All rights reserved.
The hepatoma upregulated protein (HURP) represents a putative oncogene that is overexpressed in many human cancers, especially hepatocellular carcinoma (HCC). HURP plays an important role during mitotic spindle formation, a process that is targeted by various anti-cancer drugs like taxol. However, the role of HURP during the establishment of taxol chemoresistance in HCC remains unclear. In this study, we observed that high HURP protein level correlates with taxol resistance in HCC cells. Following HURP knockdown, HCC cells show a more sensitive response to taxol treatment. Notably, sorafenib, a tyrosine kinase inhibitor approved for the treatment of HCC, inhibits HURP expression primarily at the transcriptional level and sensitizes HCC cells to sub-lethal doses of taxol. By using real-time PCR and chromatin immunoprecipitation assays, we observed that the NF-kappa B family member c-Rel represents a putative transcription factor that activates HURP gene expression. In addition, the inhibitory effect of sorafenib on HURP expression was attributed to a reduced translation and nuclear translocation of c-Rel. Accordingly, downregulation of c-Rel using short-hairpin RNA was shown to reduce HURP protein level and enhance taxol-induced cell death. Taken together, our results indicate that HURP acts as a novel survival protein that protects HCC cells against taxol-induced cell death. In addition, the regulation of HURP gene expression by NF-kappa B signaling appears to be critical for the response of HCC cells to taxol. (C) 2011 Elsevier Inc. All rights reserved.