Sorafenib down-regulates c-IAP expression post-transcriptionally in hepatic carcinoma cells to suppress apoptosis
Sorafenib down-regulates c-IAP expression post-transcriptionally in hepatic carcinoma cells to suppress apoptosis
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DOI：
10.1016/j.bbrc.2012.01.060
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发表时间：
2012-02-17
影响因子：
3.1
通讯作者：
Shi, Le-hua
中科院分区：
文献类型：
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作者：
Li, Xi-feng;Gong, Ren-yan;Shi, Le-hua
肝细胞癌（HCC）是癌症相关死亡的主要原因之一，具有异质性患者人口统计学和不同的致病途径。索拉非尼是第一个被批准用于治疗HCC的有效药物。尽管索拉非尼促进HCC细胞凋亡是已知的，但其潜在的机制仍然很不清楚。在这里，我们报告索拉非尼在体外和体内以时间和剂量依赖性方式下调HCC细胞中抗凋亡蛋白c-IAP 1的蛋白表达。此外，我们证明索拉非尼抑制c-IAP 1水平，而不改变其转录或蛋白质稳定性。相反，索拉非尼通过靶向c-IAP 1 mRNA内的内部核糖体进入位点（IRES）来减弱c-IAP 1翻译。最后，c-IAP 1的异位表达证实了索拉非尼诱导的癌细胞凋亡。总之，我们的数据突出了一个以前未确定的途径，有助于索拉非尼介导的肝癌细胞凋亡，并因此提供了新的机制，合理使用索拉非尼治疗肝癌的见解。(C)2012 Elsevier Inc. All rights reserved.
Hepatocellular carcinoma (HCC) is one of leading causes of cancer-related death with a heterogeneous patient demographic and divergent pathogenic pathways. Sorafenib is the first effective drug approved for the treatment of HCC. Although it is known that sorafenib promotes apoptosis of HCC cells, the underlying mechanism remains largely obscure. Here we report that sorafenib down-regulates protein expression of the anti-apoptotic protein c-IAP1 in a time- and dose-dependent manner in HCC cells in vitro and in vivo. Furthermore, we demonstrate that sorafenib represses c-IAP1 levels without altering its transcription or protein stability. Instead, sorafenib attenuates c-IAP1 translation by targeting the internal ribosome entry site (IRES) within the c-IAP1 mRNA. Finally, ectopic expression of c-IAP1 alleviates sorafenib induced cancer cell apoptosis. In conclusion, our data highlight a previously unidentified pathway that contributes to sorafenib mediated HCC cell apoptosis and as such provide novel mechanistic insight into the rational use of sorafenib in treating HCC. (C) 2012 Elsevier Inc. All rights reserved.