Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, China.
Biochem Biophys Res Commun. 2013 Apr 26;434(1):35-41. doi: 10.1016/j.bbrc.2013.03.070. Epub 2013 Mar 29.
The treatment of hepatocellular carcinoma (HCC) remains a challenge and the future of cancer therapy will incorporate rational combinations directed to molecular targets that cooperate to drive critical pro-survival signaling. Sphingosine kinase 1 (SphK1) has been shown to regulate various processes important for cancer progression. Given the up-regulated expression of SphK1 in response to the silence of N-ras and other interactions between Ras/ERK and SphK1, it was speculated that combined inhibition of Ras/ERK and SphK1 would create enhanced antitumor effects. Experimental results showed that dual blockage of N-ras/ERK and SphK1 resulted in enhanced growth inhibitions in human hepatoma cells. Similarly, MEK1/2 Inhibitor U0126 potentiated SKI II-induced apoptosis in hepatoma HepG2 cells, consistently with the further attenuation of Akt/ERK/NF-κB signaling pathway. It was also shown that the combination of SKI II and U0126 further attenuated the migration of hepatoma HepG2 cells via FAK/MLC-2 signaling pathway. Taken together, the dual inhibition of SphK1 and Ras/ERK pathway resulted in enhanced effects, which might be an effective therapeutic approach for the treatment of HCC.
肝细胞癌（HCC）的治疗仍然是一个挑战，癌症治疗的未来将包含针对分子靶点的合理组合，这些靶点共同合作驱动关键的生存信号。已经表明，鞘氨醇激酶 1（SphK1）调节对 N-ras 沉默的反应以及 Ras/ERK 和 SphK1 之间的其他相互作用的各种对癌症进展很重要的过程。推测 Ras/ERK 和 SphK1 的联合抑制将产生增强的抗肿瘤作用。实验结果表明，N-ras/ERK 和 SphK1 的双重阻断导致人肝癌细胞的生长抑制增强。同样，MEK1/2 抑制剂 U0126 增强了 SKI II 在肝癌 HepG2 细胞中诱导的凋亡，与 Akt/ERK/NF-κB 信号通路的进一步衰减一致。还表明，SKI II 和 U0126 的组合通过 FAK/MLC-2 信号通路进一步减弱肝癌 HepG2 细胞的迁移。总之，SphK1 和 Ras/ERK 通路的双重抑制导致增强的效果，这可能是治疗 HCC 的有效治疗方法。
