Liu Xuejiao, Cai Wei, Niu Mingshan, Chong Yulong, Liu Huize, Hu Wenqiang, Wang Dacheng, Gao Shangfeng, Shi Qiong, Hu Jinxia, Zhou Xiuping, Yu Rutong
Institute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
J Neurooncol. 2015 Feb;121(3):469-77. doi: 10.1007/s11060-014-1664-2. Epub 2014 Dec 21.
Plumbagin, a natural quinonoid constituent isolated from the root of medicinal plant Plumbago zeylanica L, has exhibited anti-tumor and anti-proliferative activities in various tumor cell lines as well as in animal tumor models. However, its anticancer effects and the mechanisms underlying its suppression of glioma cell growth have not been elucidated. Oncogenic transcription factor Forkhead Box M1 (FOXM1) has garnered particular interest in recent years as a potential target for the prevention and/or therapeutic intervention in glioma, nevertheless, less information is currently available regarding FOXM1 inhibitor. Here, we reported that plumbagin could effectively inhibit cell proliferation, migration and invasion and induce apoptosis of glioma cells. Cell cycle assay showed that plumbagin induced G2/M arrest. Interestingly, we found that plumbagin decreased the expression of FOXM1 both at mRNA level and protein level. Plumbagin also inhibited the transactivation ability of FOXM1, resulting in down-regulating the expression of FOXM1 downstream target genes, such as cyclin D1, Cdc25B, survivin, and increasing the expression of p21(CIP1) and p27(KIP1). Most importantly, down-regulation of FOXM1 by siFOXM1 transfection enhanced plumbagin-induced change in viability. On the contrary, over-expression of FOXM1 by cDNA transfection reduced plumbagin-induced glioma cell growth inhibition. These results suggest that plumbagin exhibits its anticancer activity partially by inactivation of FOXM1 signaling pathway in glioma cells. Our findings indicate that plumbagin may be considered as a potential natural FOXM1 inhibitor, which could contribute to the development of new anticancer agent for therapy of gliomas.
白花丹醌是从药用植物白花丹的根中分离出的一种天然醌类成分，在多种肿瘤细胞系以及动物肿瘤模型中均表现出抗肿瘤和抗增殖活性。然而，其抗癌作用及其抑制胶质瘤细胞生长的潜在机制尚未阐明。致癌转录因子叉头框M1（FOXM1）作为胶质瘤预防和/或治疗干预的潜在靶点，近年来备受关注，不过，目前关于FOXM1抑制剂的信息较少。在此，我们报道白花丹醌可有效抑制胶质瘤细胞的增殖、迁移和侵袭，并诱导其凋亡。细胞周期分析表明白花丹醌可诱导G2/M期阻滞。有趣的是，我们发现白花丹醌在mRNA水平和蛋白质水平均降低了FOXM1的表达。白花丹醌还抑制了FOXM1的反式激活能力，导致其下游靶基因如细胞周期蛋白D1、细胞分裂周期蛋白25B、生存素的表达下调，并增加了p21（CIP1）和p27（KIP1）的表达。最重要的是，通过小干扰RNA转染下调FOXM1增强了白花丹醌诱导的细胞活力变化。相反，通过cDNA转染过表达FOXM1可降低白花丹醌诱导的胶质瘤细胞生长抑制。这些结果表明白花丹醌部分通过失活胶质瘤细胞中的FOXM1信号通路发挥其抗癌活性。我们的研究结果表明白花丹醌可能被视为一种潜在的天然FOXM1抑制剂，这可能有助于开发用于治疗胶质瘤的新型抗癌药物。
