Wnt信号通路是生物早期发育过程中一个非常保守的信号通路。正常的Wnt信号通路中Wnt配体与受体Frizzled和LRP5/6结合后，可以抑制APC等组成的降解复合物，使细胞质内的β-catenin得以稳定和积累并进一步入核，通过与转录因子TCF/LEF结合，开启下游基因的转录。异常激活的Wnt信号不再受到降解复合物的调节并且与多种肿瘤发生、发展关系密切，尤其是Wnt信号中的关键分子APC突变可以直接导致结肠癌。Wnt信号通路尤其是下游的β-catenin/TCF4转录复合物是近年来兴起的一个治疗结肠癌等癌症的药靶。

2月15日，国际学术期刊Cell Research 在线发表了中科院上海生科院生化与细胞所李林研究组的最新研究成果。在这项工作中，王伟等人发现了一个新的Wnt信号通路的小分子抑制剂15-oxospiramilactone，并初步揭示了其作用机制和治疗结肠癌的潜力。

NC043 (15-oxospiramilactone) 是一个半合成的萜类化合物，其母体来源于一种用来消炎止疼的传统中草药Spiraea japonica。实验证明NC043通过调节内源β-catenin/TCF4转录复合物的形成有效地抑制Wnt下游靶基因的表达。NC043可以使结肠癌细胞阻滞在G2/M期，并且对于结肠癌细胞的生长的抑制明显大于正常结肠上皮细胞。移植瘤实验证明NC043可以在很低剂量就对结肠癌细胞形成的移植肿瘤起到很好的抑制效果同时对老鼠体重没有影响。这些实验结果表明NC043有可能成为一个治疗结肠癌的药物先导化合物。关于其直接作用的靶点和成药性的研究正在进行当中。

该研究课题与中科院昆明植物所郝小江研究组合作完成，获得国家科技部、国家自然科学基金委和上海市科委的经费资助。该成果已申请了相关专利。

原文出处：

Cell Research advance online publication 15 February 2011; doi: 10.1038/cr.2011.30

A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis

Wei Wang1, Haiyang Liu2, Sheng Wang1, Xiaojiang Hao2 and Lin Li1

Abstract

The Wnt/β-catenin signaling pathway is a highly conserved pathway in organism evolution and regulates many biological processes. Aberrant activation of the Wnt/β-catenin signaling pathway is closely related to tumorigenesis. In order to identify potent small molecules to treat the over-activated Wnt signaling-mediated cancer, such as colon cancer, we established a mammalian cell line-based reporter gene screening system. The screen revealed a diterpenoid derivative, 15-oxospiramilactone (NC043) that inhibits Wnt3a or LiCl-stimulated Top-flash reporter activity in HEK293T cells and growth of colon cancer cells, SW480 and Caco-2. Treatment of SW480 cells with NC043 led to decreases in the mRNA and/or protein expression of Wnt target genes Axin2, Cyclin D1 and Survivin , as well as decreases in the protein levels of Cdc25c and Cdc2. NC043 did not affect the cytosol-nuclear distribution and protein level of soluble β-catenin, but decreased β-catenin/TCF4 association in SW480 cells. Moreover, NC043 inhibited anchorage-independent growth and xenograft tumorigenesis of SW480 cells. Collectively these results demonstrate that NC043 is a novel small molecule that inhibits canonical Wnt signaling downstream of β-catenin stability and may be a potential compound for treating colorectal cancer.

Keywords: Wnt; small molecule; inhibitor; tumorigenesis