Down-regulation of FoxM1 by thiostrepton or small interfering RNA inhibits proliferation, transformation ability and angiogenesis, and induces apoptosis of nasopharyngeal carcinoma cells

摘要

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southern China. Forkhead box M1 (FoxM1) transcription factor has been shown to play important role in the development and progression of human cancers. We have previously found that FoxM1 was overexpressed in NPC patients and was associated with development of NPC. However, the exact functional significance of FoxM1 and its inhibitor thiostrepton in NPC is little known. The purpose of this study was to investigate in vitro activity of down-regulation of FoxM1 by thiostrepton or siRNA against NPC cell line. FoxM1 inhibition by thiostrepton or siRNA inhibited proliferation of NPC cells by down-regulation of cyclin D1 and cyclin E1. Transformation ability of NPC cells was suppressed by thiostrepton. FoxM1 inhibition by thiostrepton induced apoptosis of NPC cells by down-regulation of bcl-2, up-regulation of bax and p53, and inducing release of cytochrome c accompanied by activation of caspase-9, cleaved caspase-3 and cleaved PARP. In addition, FoxM1 inhibition by siRNA transfection also down-regulated expression of bcl-2 and up-regulated expression of bax, p53, cleaved caspase-3 and cleaved PARP. Furthermore, FADD and cleaved caspase-8 expression were up-regulated by thiostrepton or FoxM1 siRNA, and expression of cIAP1 and XIAP was inhibited by thiostrepton. At last, FoxM1 inhibition by thiostrepton reduced the expression of HIF-1α and VEGF, and transfection of FoxM1 siRNA decreased VEGF expression but not HIF-1α. Collectively, our finding suggest that FoxM1 inhibition by thiostrepton or siRNA suppresses proliferation, transformation ability, angiogenesis, and induces apoptosis of NPC.