Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Mol Cancer Ther. 2011 May;10(5):892-901. doi: 10.1158/1535-7163.MCT-10-0794. Epub 2011 Mar 10.
Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration- and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008-induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008-induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A.
先前，我们已经证明硼替佐米通过抑制 Akt 克服了肝癌（HCC）细胞中 TRAIL 的耐药性。在这里，我们报告硼替佐米使这些 TRAIL 耐药细胞（包括 Huh-7、Hep3B 和 Sk-Hep1）对 CS-1008（一种人源化激动性抗人死亡受体 5 抗体）敏感。癌性蛋白磷酸酶 2A 抑制剂（CIP2A）通过抑制蛋白磷酸酶 2A（PP2A）活性介导硼替佐米对 CS-1008 的增敏作用。硼替佐米和 CS-1008 的联合治疗以浓度和时间依赖的方式下调 HCC 细胞中的 CIP2A，并增加 PP2A 活性。重要的是，CIP2A 的异位表达降低了 Akt 相关的 PP2A 活性，表明 CIP2A 负调节 HCC 细胞中 Akt 相关的 PP2A 活性。此外，通过短发夹 RNA 沉默 CIP2A 增强了 HCC 细胞中 CS-1008 诱导的细胞凋亡，而 HCC 细胞中 CIP2A 的异位表达则消除了 CS-1008 诱导的细胞凋亡，表明 CIP2A 在硼替佐米对 CS-1008 的增敏作用中发挥重要作用。最后，我们的体内数据表明 CS-1008 和硼替佐米联合治疗显著降低了肿瘤生长。总之，硼替佐米通过抑制 CIP2A 使 HCC 细胞对 CS-1008 敏感。
