A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis
Liang Fang,Qionghua Zhu,Martin Neuenschwander,Edgar Specker,Annika Wulf-Goldenberg,William I. Weis,Jens Peter von Kries,Walter Birchmeier +7 more
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TLDR
The results strongly suggest that LF3 is a specific inhibitor of canonical Wnt signaling with anticancer activity that warrants further development for preclinical and clinical studies as a novel cancer therapy.Abstract:
Wnt/β-catenin signaling is a highly conserved pathway essential for embryogenesis and tissue homeostasis. However, deregulation of this pathway can initiate and promote human malignancies, especially of the colon and head and neck. Therefore, Wnt/β-catenin signaling represents an attractive target for cancer therapy. We performed high-throughput screening using AlphaScreen and ELISA techniques to identify small molecules that disrupt the critical interaction between β-catenin and the transcription factor TCF4 required for signal transduction. We found that compound LF3, a 4-thioureido-benzenesulfonamide derivative, robustly inhibited this interaction. Biochemical assays revealed clues that the core structure of LF3 was essential for inhibition. LF3 inhibited Wnt/β-catenin signals in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. LF3 also suppressed features of cancer cells related to Wnt signaling, including high cell motility, cell-cycle progression, and the overexpression of Wnt target genes. However, LF3 did not cause cell death or interfere with cadherin-mediated cell-cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as examined by sphere formation of colon and head and neck cancer stem cells under nonadherent conditions. Finally, LF3 reduced tumor growth and induced differentiation in a mouse xenograft model of colon cancer. Collectively, our results strongly suggest that LF3 is a specific inhibitor of canonical Wnt signaling with anticancer activity that warrants further development for preclinical and clinical studies as a novel cancer therapy.read more
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Targeting the Wnt/β-catenin signaling pathway in cancer.
TL;DR: This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types and better understanding of the updates on the inhibitors, antagonists and activators rationalizes innovative strategies for personalized cancer treatment.
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Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)
TL;DR: Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis.
Journal ArticleDOI
Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer
TL;DR: The role of Wnt/β-catenin signaling in CRC and its potential as a target of innovative therapeutic approaches for CRC are discussed.
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WNT Signaling in Cardiac and Vascular Disease
Sébastien Foulquier,Evangelos P. Daskalopoulos,Gentian Lluri,Kevin C.M. Hermans,Arjun Deb,W. Matthijs Blankesteijn +5 more
TL;DR: A general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology, and a rapidly increasing collection of drugs interfering at different levels of W NT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future.
Journal ArticleDOI
WNT signalling in prostate cancer
TL;DR: Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression.
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TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
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The Wnt signaling pathway in development and disease.
Catriona Y. Logan,Roel Nusse +1 more
TL;DR: The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels, and that receptor-ligand specificity and feedback loops help to determine WNT signaling outputs.
Journal ArticleDOI
Wnt/beta-catenin signaling in development and disease.
TL;DR: A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades, finding that Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.
Journal ArticleDOI
Crypt stem cells as the cells-of-origin of intestinal cancer
Nick Barker,Rachel A. Ridgway,Johan H. van Es,Marc van de Wetering,Harry Begthel,Maaike van den Born,Esther Danenberg,Alan Richard Clarke,Owen J. Sansom,Hans Clevers +9 more
TL;DR: It is concluded that stem-cell-specific loss of Apc results in progressively growing neoplasia in long-lived intestinal stem cells.
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.
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