Identification and Characterization of a Novel Small-Molecule Inhibitor of β-Catenin Signaling

Delgado, Evan R.; Yang, Jing; So, Juhoon; Fanti, Maura; Leimgruber, Stephanie; Kahn, Michaël; Ishitani, Tohru; Shin, Donghun; Wilson, George P.; Monga, Satdarshan P.

doi:10.1016/j.ajpath.2014.04.002

Cited by 30 publications

(21 citation statements)

References 31 publications

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“…Interesting β -catenin inhibitors that could have clinical applications include ICG-001 or its derivative PRI-724, PMED-1, and others. 146–148 Anti-sense and small inhibitor RNAs also might be used to reduce levels of β -catenin in HCCs or other tumor types. In a recent study, β -catenin reduction in CTNNB1 -mutated HCCs in a murine model led to complete tumor response, showing a clear benefit of therapeutic targeting of this molecule.…”

Section: Future Directionsmentioning

confidence: 99%

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis

2015

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β -catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics.

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Section: Future Directionsmentioning

confidence: 99%

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis

2015

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“…Among these strategies, inhibition of oncogenic ␤cat activity would appear to be the most direct approach, as studies have demonstrated that the accumulation of ␤cat is what initiates oncogenesis, and that tumors have a continued reliance on oncogenic ␤cat signaling (5). Indeed, recent promising antagonists have been identified that specifically disrupt ␤cat binding to TCF or the CBP transcriptional coactivator (6,7).…”

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confidence: 99%

The Poly(ADP-ribose) Polymerase Enzyme Tankyrase Antagonizes Activity of the β-Catenin Destruction Complex through ADP-ribosylation of Axin and APC2

Croy¹,

Fuller²,

Giannotti³

et al. 2016

Journal of Biological Chemistry

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Most colon cancer cases are initiated by truncating mutations in the tumor suppressor, adenomatous polyposis coli (APC).APC is a critical negative regulator of the Wnt signaling pathway that participates in a multi-protein "destruction complex" to target the key effector protein ␤-catenin for ubiquitin-mediated proteolysis. Prior work has established that the poly(ADPribose) polymerase (PARP) enzyme Tankyrase (TNKS) antagonizes destruction complex activity by promoting degradation of the scaffold protein Axin, and recent work suggests that TNKS inhibition is a promising cancer therapy. We performed a yeast two-hybrid (Y2H) screen and uncovered TNKS as a putative binding partner of Drosophila APC2, suggesting that TNKS may play multiple roles in destruction complex regulation. We find that TNKS binds a C-terminal RPQPSG motif in Drosophila APC2, and that this motif is conserved in human APC2, but not human APC1. In addition, we find that APC2 can recruit TNKS into the ␤-catenin destruction complex, placing the APC2/ TNKS interaction at the correct intracellular location to regulate ␤-catenin proteolysis. We further show that TNKS directly PARylates both Drosophila Axin and APC2, but that PARylation does not globally regulate APC2 protein levels as it does for Axin. Moreover, TNKS inhibition in colon cancer cells decreases ␤-catenin signaling, which we find cannot be explained solely through Axin stabilization. Instead, our findings suggest that TNKS regulates destruction complex activity at the level of both Axin and APC2, providing further mechanistic insight into TNKS inhibition as a potential Wnt pathway cancer therapy.The Wnt pathway helps direct a myriad of normal developmental and adult homeostasic processes in metazoans, but is also misregulated in several human diseases such as cancer (1, 2). Wnt signaling is regulated through the activity of a multiprotein "destruction complex" that promotes proteolysis of the transcriptional co-activator ␤-catenin (␤cat) 3 by stimulating phosphorylation of the ␤cat phosphodegron (3). Core components of the destruction complex include the scaffold protein Axin, the tumor suppressor adenomatous polyposis coli (APC), and the kinases CK1 and GSK3.While Wnt signaling plays essential roles during development, it is inappropriately activated in a number of cancers, most notably colorectal cancer. Truncating mutations in the tumor suppressor adenomatous polyposis coli (APC) are the initiating mutational event in more than 80% of all colon cancer cases, and these mutations hyperactivate ␤cat signaling (4). Thus small molecule inhibitors of the Wnt pathway should provide an effective therapeutic strategy. Among these strategies, inhibition of oncogenic ␤cat activity would appear to be the most direct approach, as studies have demonstrated that the accumulation of ␤cat is what initiates oncogenesis, and that tumors have a continued reliance on oncogenic ␤cat signaling (5). Indeed, recent promising antagonists have been identified that specifically disrupt ␤cat binding to TCF or th...

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“…Currently, a second-generation compound of ICG-001, PRI-724, is in multiple Phase I and Phase II trials for pancreatic adenocarcinoma, solid tumors and for myeloid malignancies respectively (NCT01764477) (NCT01302405) (NCT01606579). Recently, we have also utilized structure-function analysis to identify ICG-001 like molecule PMED-1, which suppresses β-catenin activity in HCC cells and in zebrafish [9]. In current study we used LNA to target β-catenin expression.…”

Section: Discussionmentioning

confidence: 99%

“…Hep3B HCC cells stably transfected with serine-33 to tyrosine mutated (S33Y) β-catenin described recently, were grown to approximately 70% confluency and serum-starved for 24h [8, 9, 19, 26]. Cells were then transfected with 800ng of TopFlash plasmid (Millipore), 200ng of Renilla, and 3 μl of lipofectamine 2000 in 100μl Optimem media.…”

Section: Methodsmentioning

confidence: 99%

Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model

Delgado

Okabe

Preziosi

et al. 2015

Journal of Hepatology

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Background and Aims Hepatocellular cancer (HCC) remains a disease of poor prognosis highlighting the relevance of elucidating key molecular aberrations that may be targeted for novel therapies. Wnt signaling activation chiefly due to mutations in CTNNB1 have been identified in a major subset of HCC patients. While several in vitro proof-of-concept studies show the relevance of suppressing Wnt/β-catenin signaling in HCC cells or tumor xenograft models, no study has addressed the impact of β-catenin inhibition in a relevant murine HCC model driven by CTNNB1 mutations. Methods We studied the in vivo impact of β-catenin suppression by locked nucleic acid (LNA) antisense treatment after establishing CTNNB1 mutations-driven HCC by Diethylnitrosamine and Phenobarbital (DEN/PB) administration. Results The efficacy of LNA-directed against β-catenin versus scrambled sequence on Wnt signaling was demonstrated in vitro in HCC cells and in vivo in normal mice. DEN/PB model led to HCC with CTNNB1 mutations. A complete therapeutic response in the form of abrogation of HCC was observed after ten treatments of tumor-bearing mice with β-catenin LNA every 48 hours as compared to the scrambled control. A decrease in β-catenin activity, cell proliferation and increased cell death was evident after β-catenin suppression. No effect of β-catenin suppression was evident in non-CTNNB1 mutated HCC observed after DEN only administration. Conclusions Thus, we provide in vivo proof-of-concept that β-catenin suppression in HCC will be of significant therapeutic benefit provided the tumors display Wnt activation via mechanisms like CTNNB1 mutations.

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Identification and Characterization of a Novel Small-Molecule Inhibitor of β-Catenin Signaling

Cited by 30 publications

References 31 publications

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis

The Poly(ADP-ribose) Polymerase Enzyme Tankyrase Antagonizes Activity of the β-Catenin Destruction Complex through ADP-ribosylation of Axin and APC2

Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model

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