Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Br J Pharmacol. 2013 Feb;168(3):658-72. doi: 10.1111/j.1476-5381.2012.02212.x.
Previously, we have shown that sorafenib sensitizes hepatocellular carcinoma (HCC) to apoptosis induced by TNF-related apoptosis-inducing ligand (TNFSF10; TRAIL). Here, we report that sorafenib and SC-49 sensitize HCC cells to CS-1008, a novel anti-human death receptor 5 (TNFRSF10B) antibody.
HCC cell lines (PLC5, Huh-7, and Hep3B) were treated with CS-1008 and/or sorafenib and analysed in terms of apoptosis and signal transductions.
SC-49 is a sorafenib derivative, which is devoid of kinase inhibitory activity. Both sorafenib and SC-49 down-regulated the phosphorylation of STAT3 at Tyr(705) and subsequently reduced the levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in CS-1008-treated HCC cells. Knockdown of STAT3 by RNA interference overcame apoptotic resistance to CS-1008 in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effects of sorafenib and SC-49 on CS-1008-induced apoptosis, indicating that inhibition of STAT3 mediates the enhancing effects of these compounds when combined with CS-1008. Importantly, inhibition of SHP-1 by adding a specific SHP-1 inhibitor reduced the effects of SC-49 and CS-1008 on p-STAT3 and apoptosis, whereas co-treatment of CS-1008 with SC-49 increased the activity of SHP-1. These data indicate that the combined effects of CS-1008 and SC-49 on HCC are mediated by SHP-1. Moreover, the combination of CS-1008 and SC-49 inhibited HCC xenograft tumour growth in vivo.
Sorafenib and its derivative SC-49 sensitize HCC cells to the antitumour effects of CS-1008 through SHP-1-dependent inactivation of STAT3.
此前，我们已证实索拉非尼可增强肿瘤坏死因子相关凋亡诱导配体（TNFRSF10；TRAIL）诱导的肝细胞癌（HCC）细胞凋亡。本研究旨在报道索拉非尼和 SC-49 可增强 HCC 细胞对新型抗人死亡受体 5（TNFRSF10B）抗体 CS-1008 的敏感性。
采用 CS-1008 和/或索拉非尼处理 HCC 细胞系（PLC5、Huh-7 和 Hep3B），并分析其凋亡和信号转导情况。
SC-49 是索拉非尼的衍生物，其无激酶抑制活性。索拉非尼和 SC-49 均可使 CS-1008 处理的 HCC 细胞中 STAT3 的 Tyr（705）磷酸化水平下调，随后降低 STAT3 调节蛋白 Mcl-1、survivin 和 cyclin D1 的水平。STAT3 RNA 干扰可克服 HCC 细胞对 CS-1008 的抗凋亡作用，HCC 细胞中 STAT3 的异位表达可消除索拉非尼和 SC-49 对 CS-1008 诱导的凋亡的增敏作用，表明抑制 STAT3 介导了这些化合物与 CS-1008 联合应用时的增强作用。重要的是，通过添加特定的 SHP-1 抑制剂抑制 SHP-1 可降低 SC-49 和 CS-1008 对 p-STAT3 和凋亡的影响，而 CS-1008 与 SC-49 联合治疗可增加 SHP-1 的活性。这些数据表明，CS-1008 和 SC-49 对 HCC 的联合作用是由 SHP-1 介导的。此外，CS-1008 和 SC-49 的联合治疗可抑制体内 HCC 异种移植肿瘤的生长。
索拉非尼及其衍生物 SC-49 通过 SHP-1 依赖性 STAT3 失活增强 HCC 细胞对 CS-1008 的抗肿瘤作用。
