A Novel Inhibitor of Wnt/β-catenin Signaling and Colon Cancer Cell Tumorigenesis
Source:
Time: 2011-03-04
A team of researchers led by LI Lin at Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, found a diterpenoid derivative, 15-oxospiramilactone, which inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis.
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 this work, WANG Wei and colleagues found 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.
This work entitled ‘A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis’ was published online in Cell Research on February 15, 2011. This work was collaborated with HAO Xiaojiang (Kunming Institute of Botany) and supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality. (SIBCB)
AUTHOR CONTACT:
LI Lin
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
NC043 inhibits SW480 cell tumorigenesis in vitro and in vivo. (A, B) NC043 but not its derivatives inhibit anchorage-independent growth of SW480 cells. SW480 cells were seeded in soft agar with NC043 (A) and its derivatives (B) for 18 days and stained with crystal violet. Data represent the mean±S.E. from three independent experiments. (C-F) NC043 inhibits SW480 cell tumorigenesis in a xenograft model. Tumor bearing mice were treated intraperitoneally with either vehicle or NC043 (45 and 90 μg/kg) daily for 17 days. Body weight (C), tumor size (E) and tumor weight (F) were measured as described in Materials and Methods. The external appearance of tumors is shown (D). Data represent the mean±S.E., * P < 0.05, ** P < 0.01, significant relative to vehicle control.
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