CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells
CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells
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DOI：
10.1038/onc.2010.357
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发表时间：
2010-11-01
期刊：
影响因子：
8
通讯作者：
Cheng, A-L
中科院分区：
文献类型：
--
作者：
Chen, K-F;Liu, C-Y;Cheng, A-L
此前，我们报道过 Akt 失活决定了肝细胞癌 (HCC) 细胞对硼替佐米的敏感性。在这项研究中，我们报告癌性蛋白磷酸酶 2A 抑制剂 (CIP2A)，一种蛋白磷酸酶 2A (PP2A) 的细胞抑制剂，介导硼替佐米在 HCC 中的细胞凋亡作用。通过小干扰 RNA (siRNA) 沉默 PP2A 可消除硼替佐米诱导的磷酸 Akt 下调和细胞凋亡。 Bortezomib 会增加敏感 HCC 细胞（包括 Sk-Hep1、Hep3B 和 Huh-7）中的 PP2A 活性，但不会增加耐药性 PLC5 细胞中的 PP2A 活性。 Bortezomib 在所有敏感 HCC 细胞中以剂量和时间依赖性方式下调 CIP2A，而在耐药 PLC5 细胞中未发现 CIP2A 发生改变。 siRNA 敲低 CIP2A 可恢复硼替佐米对 PLC5 细胞凋亡和 PP2A 活性的影响。此外，CIP2A 的过度表达上调磷酸 Akt 并保护 Sk-Hep1 细胞免受硼替佐米诱导的细胞凋亡。值得注意的是，CIP2A 的异位表达降低了 Akt 相关的 PP2A 活性，而沉默 CIP2A 则增加了该活性，表明 CIP2A 负向调节 HCC 细胞中 Akt 相关的 PP2A 活性，此外，我们的体内数据表明，硼替佐米在 Huh-7 肿瘤中下调 CIP2A 并上调 PP2A 活性，但在 PLC5 肿瘤中则不然。总之，CIP2A 的抑制决定了硼替佐米对 HCC 细胞凋亡和 PP2A 依赖性 Akt 失活的影响。癌基因 (2010) 29, 6257-6266; doi：10.1038/onc.2010.357； 2010 年 8 月 23 日在线发布
Previously, we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib. In this study, we report that cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediates the apoptotic effect of bortezomib in HCC. Silencing PP2A by small interference RNA (siRNA) abolishes bortezomib-induced down-regulation of phospho-Akt and apoptosis. Bortezomib increases PP2A activity in sensitive HCC cells, including Sk-Hep1, Hep3B and Huh-7, but not in resistant PLC5 cells. Bortezomib down-regulates CIP2A in a dose-and time-dependent manner in all sensitive HCC cells, whereas no alterations in CIP2A were found in resistant PLC5 cells. Knockdown of CIP2A by siRNA restored bortezomib's effects on apoptosis and PP2A activity in PLC5 cells. Moreover, over-expression of CIP2A up-regulated phospho-Akt and protected Sk-Hep1 cells from bortezomib-induced apoptosis. It is significant that, ectopic expression of CIP2A decreased Akt-related PP2A activity, whereas silencing CIP2A increased this activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells, furthermore, our in vivo data showed that bortezomib down-regulates CIP2A and up-regulates PP2A activity in Huh-7 tumors, but not in PLC5 tumors. In conclusion, inhibition of CIP2A determines the effects of bortezomib on apoptosis and PP2A-dependent Akt inactivation in HCC. Oncogene (2010) 29, 6257-6266; doi:10.1038/onc.2010.357; published online 23 August 2010