A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice

Waaler, Jo; Machoň, Ondřej; Tůmová, Lucie; Dinh, Huyen; Kor̆ínek, Vladimír; Wilson, Steven Ray; Paulsen, Jan Erik; Pedersen, Nina Marie; Eide, Tor J.; Machoňová, Olga; Gradl, Dietmar; Voronkov, Andrey; Kries, Jens Peter von; Krauß, Stefan

doi:10.1158/0008-5472.can-11-3336

Cited by 293 publications

(287 citation statements)

References 49 publications

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“…Several research groups have identified small molecules that inhibit Tankyrases and correspondingly Wnt/ -catenin signaling ( Table 1) by stabilizing the destruction complex [37][38][39][40], [165,166].…”

Section: Tankyrasesmentioning

confidence: 99%

“…These compounds usually have stacking interactions with the side chain of Tyr1071 and form two hydrogen bonds with Gly1032 (numbering for human Tankyrase 2). Tankyrase inhibitors that bind to the ADP pocket include IWR1, JW55, and JW74 ( Table 1) [38][39][40]. These molecules participate in stacking interactions with the side chain of histidine (aa 1201 in Tankyrase 1, aa 1048 in Tankyrase 2) and in hydrogen bonding with the backbone amides of Tyr1213 (Tyr1060 in Tankyrase 2) and Asp1198 (Asp1045 in Tankyrase 2) in the adenine dinucleotide pocket (PDB structures in Protein Data Bank, www.rcsb.org: 1UDD, 1UA9 and 4DVI) [167][168][169].…”

Section: Tankyrasesmentioning

confidence: 99%

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Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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Section: Tankyrasesmentioning

confidence: 99%

Section: Tankyrasesmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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“…22). Reduction in the production of the AXIN2 protein was also observed, indicating that monensin did not inhibit tankyrase (14). In contrast, monensin had no effect on the cellular levels of nuclear Wnt signaling effector TCF4 (Fig.…”

Section: Monensin Inhibits the Wnt Signaling Cascade At Multiple Levelsmentioning

confidence: 84%

“…5A). Stained tumors contrasted with the healthy mucosa enabled quantitative analysis of the tumor size and numbers using the image analysis software Ellipse (14). Although the numbers of tumors did not change substantially, a significant (P ¼ 0.0144) reduction in the average size of lesions was observed in monensin-treated Apc þ/Min mice when compared with control animals (mean 0.199 mm 2 vs. 0.299 mm 2 ).…”

Section: Monensin Reduces Tumor Size In the Apcmentioning

confidence: 99%

Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice

Tůmová

Pombinho

Vojtěchová

et al. 2014

Molecular Cancer Therapeutics

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The Wnt signaling pathway is required during embryonic development and for the maintenance of homeostasis in adult tissues. However, aberrant activation of the pathway is implicated in a number of human disorders, including cancer of the gastrointestinal tract, breast, liver, melanoma, and hematologic malignancies. In this study, we identified monensin, a polyether ionophore antibiotic, as a potent inhibitor of Wnt signaling. The inhibitory effect of monensin on the Wnt/b-catenin signaling cascade was observed in mammalian cells stimulated with Wnt ligands, glycogen synthase kinase-3 inhibitors, and in cells transfected with b-catenin expression constructs. Furthermore, monensin suppressed the Wnt-dependent tail fin regeneration in zebrafish and Wnt-or b-catenin-induced formation of secondary body axis in Xenopus embryos. In Wnt3a-activated HEK293 cells, monensin blocked the phoshorylation of Wnt coreceptor low-density lipoprotein receptor related protein 6 and promoted its degradation. In human colorectal carcinoma cells displaying deregulated Wnt signaling, monensin reduced the intracellular levels of b-catenin. The reduction attenuated the expression of Wnt signaling target genes such as cyclin D1 and SP5 and decreased the cell proliferation rate. In multiple intestinal neoplasia (Min) mice, daily administration of monensin suppressed progression of the intestinal tumors without any sign of toxicity on normal mucosa. Our data suggest monensin as a prospective anticancer drug for therapy of neoplasia with deregulated Wnt signaling. Mol Cancer Ther; 13(4); 812-22. Ó2014 AACR.

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“…The techniques were performed as described previously (Doubravska et al ., 2011; Waaler et al ., 2012). For immunohistochemistry, dissected intestines were washed in ice‐cold PBS, fixed overnight in 4% (v/v) formaldehyde (Penta) and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

Janečková

Fafílek

Krausová

et al. 2016

Genesis

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SummaryThe Wnt pathway plays a crucial role in self‐renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N‐terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild‐type (wt) TCF4 protein decreased transcription of β‐catenin‐TCF4‐responsive genes. Interestingly, suppression of Wnt/β‐catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC‐specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc‐deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell‐autonomous inhibition of β‐catenin‐Tcf‐mediated transcription. genesis 54:101–114, 2016. © 2016 The Authors genesis Published by Wiley Periodicals, Inc.

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A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice

Cited by 293 publications

References 49 publications

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

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