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

Cell Res. 2011 May;21(5):730-40. doi: 10.1038/cr.2011.30. Epub 2011 Feb 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Diterpenes / pharmacology*
  • G2 Phase / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Mitosis / drug effects
  • Precancerous Conditions / pathology*
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Signal Transduction / drug effects*
  • Transcription Factor 4
  • Transcription Factors / metabolism
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*


  • 15-oxospiramilactone
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Diterpenes
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin