An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway
Foster C. Gonsalves,Keren Klein,Brittany Carson,Shauna Katz,Laura A. Ekas,Steve S. Evans,Robert A. Nagourney,Timothy Cardozo,Anthony M. C. Brown,Ramanuj DasGupta +9 more
TLDR
In this paper, an RNAi-based modifier screening strategy was used to identify Wnt/β-catenin-induced target genes and phenotypes in various mammalian and cancer cell lines.Abstract:
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.read more
Citations
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WNT signalling pathways as therapeutic targets in cancer
Jamie N. Anastas,Randall T. Moon +1 more
TL;DR: This work has shown that WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis, and improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models.
Journal ArticleDOI
Can we safely target the WNT pathway
TL;DR: The problems and potential solutions to the vexing situation of aberrant regulation of the WNT pathway are examined and a attempt is made to bring them into perspective.
Journal ArticleDOI
Tackling the cancer stem cells — what challenges do they pose?
TL;DR: The signalling pathways that create cancer stem cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them are discussed.
Journal ArticleDOI
Mechanical strain induces E-cadherin–dependent Yap1 and β-catenin activation to drive cell cycle entry
TL;DR: It is shown that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle reentry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then β-catenin, and cadherins provide signaling centers required for cellular responses to externally applied force.
Journal ArticleDOI
Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms.
TL;DR: The Wnt-activating mechanisms in CRC are discussed, the current advances and challenges in drug discovery are reviewed, and many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations are revealed.
References
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Journal ArticleDOI
Wnt signaling and cancer
TL;DR: In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.
Journal ArticleDOI
Wnt proteins are lipid-modified and can act as stem cell growth factors
Karl Willert,Jeffrey Brown,Esther Danenberg,Andrew W. Duncan,Irving L. Weissman,Tannishtha Reya,John R. Yates,Roel Nusse +7 more
TL;DR: This work isolated active Wnt molecules, including the product of the mouse Wnt3a gene, and found the proteins to be palmitoylated on a conserved cysteine, indicating that the lipid is important for signalling.
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Mechanisms of wnt signaling in development
Andreas Wodarz,Roel Nusse +1 more
TL;DR: Over the past two years the understanding of Wnt signaling has been substantially improved by the identification of Frizzled proteins as cell surface receptors for Wnts and by the finding that beta-catenin, a component downstream of the receptor, can translocate to the nucleus and function as a transcriptional activator.
Journal ArticleDOI
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
Shih Min A Huang,Yuji Mishina,Shanming Liu,Atwood K. Cheung,Frank Stegmeier,Gregory A. Michaud,Olga Charlat,Elizabeth Wiellette,Yue Zhang,Stephanie Wiessner,Marc Hild,Xiaoying Shi,Christine D. Wilson,Craig Mickanin,Vic E. Myer,Aleem Fazal,Ronald Tomlinson,Fabrizio C. Serluca,Wenlin Shao,Hong Cheng,Michael Shultz,Christina Rau,Markus Schirle,Judith Schlegl,Sonja Ghidelli,Stephen Fawell,Chris Lu,Daniel Curtis,Marc W. Kirschner,Christoph Lengauer,Peter Finan,John A. Tallarico,Tewis Bouwmeester,Jeffery A. Porter,Andreas Bauer,Feng Cong +35 more
TL;DR: This study uses a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits β-catenin-mediated transcription and reveals new mechanistic insights into the regulation of axin protein homeostasis, which presents new avenues for targeted Wnt pathway therapies.
Journal ArticleDOI
WNT and β-catenin signalling: diseases and therapies
TL;DR: WNT signalling has been studied primarily in developing embryos, but WNTs also have important functions in adults, and aberrant signalling by WNT pathways is linked to a range of diseases, most notably cancer.
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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
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