Wnt信號通路是生物早期發(fā)育過程中一個非常保守的信號通路,。正常的Wnt信號通路中Wnt配體與受體Frizzled和LRP5/6結(jié)合后，可以抑制APC等組成的降解復(fù)合物,，使細(xì)胞質(zhì)內(nèi)的β-catenin得以穩(wěn)定和積累并進一步入核，通過與轉(zhuǎn)錄因子TCF/LEF結(jié)合,，開啟下游基因的轉(zhuǎn)錄,。異常激活的Wnt信號不再受到降解復(fù)合物的調(diào)節(jié)并且與多種腫瘤發(fā)生、發(fā)展關(guān)系密切,，尤其是Wnt信號中的關(guān)鍵分子APC突變可以直接導(dǎo)致結(jié)腸癌,。Wnt信號通路尤其是下游的β-catenin/TCF4轉(zhuǎn)錄復(fù)合物是近年來興起的一個治療結(jié)腸癌等癌癥的藥靶。
2月15日,，國際學(xué)術(shù)期刊Cell Research 在線發(fā)表了中科院上海生科院生化與細(xì)胞所李林研究組的最新研究成果,。在這項工作中，王偉等人發(fā)現(xiàn)了一個新的Wnt信號通路的小分子抑制劑15-oxospiramilactone,，并初步揭示了其作用機制和治療結(jié)腸癌的潛力,。
NC043 (15-oxospiramilactone) 是一個半合成的萜類化合物，其母體來源于一種用來消炎止疼的傳統(tǒng)中草藥Spiraea japonica,。實驗證明NC043通過調(diào)節(jié)內(nèi)源β-catenin/TCF4轉(zhuǎn)錄復(fù)合物的形成有效地抑制Wnt下游靶基因的表達,。NC043可以使結(jié)腸癌細(xì)胞阻滯在G2/M期，并且對于結(jié)腸癌細(xì)胞的生長的抑制明顯大于正常結(jié)腸上皮細(xì)胞,。移植瘤實驗證明NC043可以在很低劑量就對結(jié)腸癌細(xì)胞形成的移植腫瘤起到很好的抑制效果同時對老鼠體重沒有影響,。這些實驗結(jié)果表明NC043有可能成為一個治療結(jié)腸癌的藥物先導(dǎo)化合物。關(guān)于其直接作用的靶點和成藥性的研究正在進行當(dāng)中,。
該研究課題與中科院昆明植物所郝小江研究組合作完成,，獲得國家科技部、國家自然科學(xué)基金委和上海市科委的經(jīng)費資助,。該成果已申請了相關(guān)專利,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
