An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway Academic Article uri icon


MeSH Major

  • Antineoplastic Agents
  • Drug Discovery
  • RNA Interference
  • Transcription, Genetic
  • Wnt Proteins
  • beta Catenin


  • Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin-induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.

publication date

  • April 12, 2011



  • Academic Article



  • eng

PubMed Central ID

  • PMC3076864

Digital Object Identifier (DOI)

  • 10.1073/pnas.1017496108

PubMed ID

  • 21393571

Additional Document Info

start page

  • 5954

end page

  • 63


  • 108


  • 15