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

• DOI: 10.1073/pnas.1017496108
• Publication Date: 2011-03-11T03:50:51Z
• Authors: Foster C. Gonsalves; Keren Klein; Brittany B. Carson; Shauna Katz; Laura A. Ekas; Steve Evans; Robert Nagourney; Timothy Cardozo; Anthony M. C. Brown; Ramanuj DasGupta
• Keywords: Adherens junction; Phenotypic screening

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 combating cancers. Despite significant effort, successful clinical implementation CRT inhibitory therapeutics remains challenging goal. This is, part, because challenge identifying compounds that specifically modulate nuclear transcriptional activity while not affecting its cytoskeletal function stabilizing adherens junctions at cell membrane. Here, we report an RNAi-based modifier screening strategy for identification inhibitors. Our data provide support specificity these antagonizing β-catenin. We show inhibitors efficiently block Wnt/β-catenin–induced genes phenotypes mammalian cancer lines. Importantly, Wnt are cytotoxic to human colon tumor biopsy cultures as well lines exhibit deregulated signaling.