Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Cancer Lett. 2012 Aug 1;321(1):27-35. doi: 10.1016/j.canlet.2012.03.023. Epub 2012 Mar 28.
We investigated the effects of a novel compound, SC-2001, on hepatocellular carcinoma (HCC). SC-2001, which is structurally related to the Mcl-1 inhibitor obatoclax, showed better antitumor effects than obatoclax in HCC cell lines, including HepG2, PLC5 and Huh-7. Like obatoclax, SC-2001 inhibited the protein-protein interactions between Mcl-1 and Bak. However, SC-2001 downregulated the protein levels of Mcl-1 by reducing its transcription whereas obatoclax had no significant effect on Mcl-1 expression. As Mcl-1 is regulated by signal transducers and activators of transcription 3 (STAT3), we found that SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited transcriptional activities of STAT3 in a dose-dependent manner. In addition to Mcl-1, STAT3-regulated proteins, including survivin and cyclin D1, were also repressed by SC-2001. Notably, SC-2001 reduced IL-6-induced STAT3 activation in HepG2 and PLC5 cells. Ectopic expression of STAT3 abolished the prominent apoptotic death in SC-2001-treated PLC5 cells, indicating that STAT3 is indispensable in mediating the effects of SC-2001. Importantly, SC-2001 enhanced the expression of SHP1, a negative regulator of STAT3. Inhibition of SHP-1 by either specific inhibitor or small interference RNA reduced the apoptotic effects of SC-2001, indicating that SHP-1 plays a key role in mediating SC2001-induced cell death. SC-2001 enhanced the activity of SHP-1 in all tested HCC cells including HepG2, PLC5 and Huh-7. Finally, SC-2001 reduced PLC5 tumor growth, downregulated p-STAT3 and upregulated SHP-1 expression and activity in vivo. In conclusion, our results suggest that SC-2001 induces apoptosis in HCC, and that this effect is mediated through SHP-1-dependent STAT3 inactivation.
我们研究了一种新型化合物 SC-2001 对肝细胞癌（HCC）的作用。SC-2001 与 Mcl-1 抑制剂 obatoclax 在结构上相关，在 HepG2、PLC5 和 Huh-7 等 HCC 细胞系中显示出比 obatoclax 更好的抗肿瘤作用。与 obatoclax 一样，SC-2001 抑制了 Mcl-1 和 Bak 之间的蛋白-蛋白相互作用。然而，SC-2001 通过降低其转录来下调 Mcl-1 的蛋白水平，而 obatoclax 对 Mcl-1 表达没有显著影响。由于 Mcl-1 受信号转导和转录激活因子 3（STAT3）调控，我们发现 SC-2001 以剂量依赖性方式下调 STAT3 的磷酸化（Tyr 705）并随后抑制 STAT3 的转录活性。除了 Mcl-1 之外，STAT3 调控的蛋白质，包括 survivin 和 cyclin D1，也被 SC-2001 抑制。值得注意的是，SC-2001 减少了 HepG2 和 PLC5 细胞中 IL-6 诱导的 STAT3 激活。STAT3 的异位表达消除了 SC-2001 处理的 PLC5 细胞中明显的凋亡死亡，表明 STAT3 在介导 SC-2001 的作用中是不可或缺的。重要的是，SC-2001 增强了 STAT3 的负调节因子 SHP1 的表达。通过特异性抑制剂或小干扰 RNA 抑制 SHP-1 减少了 SC-2001 的凋亡作用，表明 SHP-1 在介导 SC2001 诱导的细胞死亡中发挥关键作用。SC-2001 增强了所有测试的 HCC 细胞（包括 HepG2、PLC5 和 Huh-7）中 SHP-1 的活性。最后，SC-2001 减少了 PLC5 肿瘤生长，下调了 p-STAT3 并上调了体内 SHP-1 的表达和活性。总之，我们的结果表明，SC-2001 诱导 HCC 细胞凋亡，这种作用是通过 SHP-1 依赖性 STAT3 失活介导的。
