A novel sphingosine kinase 1 inhibitor (SKI-5C) induces cell death of Wilms%26apos; tumor cells in vitro and in vivo

作者:Li Zhi Heng; Tao Yan Fang; Xu Li Xiao; Zhao He; Li Xiao Lu; Fang Fang; Wu Yi; Lu Jun; Li Yan Hong; Du Wei Wei; Ren Jun Li; Li Yi Ping; Xu Yun Yun; Feng Xing; Wang Jian; He Wei Qi; Pan Jian
来源:American Journal of Translational Research, 2016, 8(11): 4548-4563.

摘要

Sphingosine kinase 1 (SphK1) is over-expressed in many cancers and therefore serves as a biomarker for cancer prognosis. SKI-5C is a new SphK1 inhibitor, and until now its molecular function in Wilms' tumor cells remained unknown. Here, using CCK-8 and nude mice experiments we assessed cell growth in Wilms' tumor cell lines (SK-NEP-1 and G401) in vitro and in vivo. We demonstrated that SphK1 is highly expressed in SK-NEP-1 and G401 cells, and through annexin V/propidium iodide staining and flow cytometry analysis, we detected cell apoptosis. Treatment with SKI-5C inhibited proliferation and induced apoptosis of SK-NEP-1 and G401 cells in a dosedependent manner. Moreover, SKI-5C treatment inhibited the growth of SK-NEP-1 xenograft tumors in nude mice, with few side effects. Our microarray analysis revealed that SKI-5C-treated SK-NEP-1 cells mostly downregulated PRKACA and significantly inhibited phosphorylation of ERK1/2 and NF-kappa B p65. These results imply that SKI-5C induces apoptosis of SK-NEP-1 cells through the PRKACA/MAPK/NF-kappa B pathway. While, further research is required to determine the underlying details, these results provide new clues for the molecular mechanism of cell death induced by SKI-5C and suggest that SKI-5C may act as new candidate drug for Wilms' tumor.