A Small Molecule Inhibitor of the β-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo

Shin, Seung Ho; Lim, Do Young; Reddy, Kanamata; Malakhova, Margarita; Liu, Fangfang; Wang, Ting; Song, Mijung; Chen, Hanyong; Bae, Ki Beom; Ryu, Joohyun; Liu, Kangdong; Lee, Mee-Hyun; Bode, Ann M.; Dong, Zigang

doi:10.1016/j.ebiom.2017.09.029

Cited by 50 publications

(42 citation statements)

References 48 publications

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“…A number of small-molecule compounds targeting TNIK, including mebendazole, an anthelmintic agent and selective inhibitor of TNIK (73), NCB-0846, a small-molecule TNIK inhibitor (73) and HI-B1, a small molecule that directly interacts with β-catenin (74), have been demonstrated to exert anti-tumor effects against various cancers. At present, mebendazole is under clinical evaluation (73).…”

Section: β-Catenin Modulators [Caudal Type Homeobox 2 (Cdx2) Huaiermentioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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Abstract. Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

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Section: β-Catenin Modulators [Caudal Type Homeobox 2 (Cdx2) Huaiermentioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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“…An alternative derived from our results is the possibility of modulating the neuronal morphology in the neurogenic niche and in a determined time frame, after PORCN inhibition by Wnt-C59, using the "replacement" of speci c Wnt ligands, and thereby avoiding other secreted endogenous Wnt inhibitors, such as Dickkopf-1 (Dkk-1) or the secreted-frizzled-related protein (sFRP), which would allow the formation of new connections and therefore new neural networks (39,55,56). An interesting example is Wnt signaling inhibition by Wnt-C59 which prevents the activity of Wnt3a and Wnt8B, in canonical and noncanonical Wnt-mediated signaling to induce cortical motor neurons or their progenitors from iPSCs in humans (26,57).…”

Section: Discussionmentioning

confidence: 99%

Morphological Neurite Changes Induced by Porcupine Inhibition Are Rescued by Wnt Ligands

Godoy

Espinoza-Caicedo

Inestrosa

2020

Preprint

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Background: Wnt signaling plays key roles in cellular and physiological processes, including cell proliferation, differentiation and migration during development and tissue homeostasis in adults. This pathway can be defined as Wnt/β-catenin-dependent or β-catenin-independent or "non-canonical", both signaling are involved in neurite and synapse development/maintenance. Porcupine (PORCN), an acylase that o-acylates Wnt ligands, a major modification in secretion and interaction with its receptors. We use Wnt-C59, a specific PORCN inhibitor, to block the secretion of endogenous Wnts in young hippocampal neurons (DIV 4). Under these conditions, the morphology and length of the neurites and the complexity of the dendritic tree and axonal polarity were evaluated. Methods: Cultured primary young hippocampal neurons obtained from Sprague-Dawley rat fetuses (E18), were cultured until day in vitro (DIV) 4 (according to Banker´s protocol) and treated with Wnt-C59 for 24h, Wnt ligands were added to the cultures on DIV 3 for 24h. Dendritic arbors and neurites were analysis by fluorescence microscopy. Transfection with Lipofectamine 2000 on DIV 2 of plasmid expressing eGFP and KIF5-Cherry and neurons were fixed on DIV 4. Immunostaining was performed with MAP1B and Tau protein. Immunoblot analysis was carried out with Wnt3a, b-catenin and GSK-3b (p-Ser9). Quantitative analysis of dendrite morphology was carried out with ImageJ (NIH) software with Neuron J Plugin.Results: We report, here, that Wnt-C59 treatment changed the morphology of the dendritic arbors and neurites of young hippocampal neurons, with decreases -catenin and Wnt3a and an increase in GSK-3 (p-Ser9) levels No effect was observed on axonal polarity. In sister cultures, addition of exogenous Wnt3a, 5a and 7a ligands rescued the changes in neuronal morphology. Wnt3a restored the length of neurites to near that of the control, but Wnt7a increased the neurite length beyond that of the control. Wnt5a also restored the length of neurites relative Wnt concentrations. Conclusions: Our results indicated that all 3 Wnt ligands restored dendritic arbor complexity with recovery of secondary and tertiary projections in young hippocampal neurons. We proposed that PORCN is an emerging molecular target of interest in the search for preclinical options to study and treat neurological diseases.

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“…β-Catenin is a critical component of the Wnt signaling pathway, which is normally inactive. And after being abnormally activated, β-catenin translocates into the nucleus where it binds competitively to TCF4, forming a β-catenin/TCF4 complex which in turn increases the transcription International Journal of Polymer Science of downstream oncogenes, including target genes c-Myc, cyclin D1, E-cadherin, and VEGF, thereby contributing to the promotion of development, invasion, and metastasis of such cancers [25,26]. For example, long noncoding RNA (ENST0000434223) reduces the proliferation, invasion, and migration of gastric cancer cells by inhibiting this pathway [27].…”

Section: Discussionmentioning

confidence: 99%

Effects of Laminaria Japonica Polysaccharides on the Survival of Non-Small-Cell Lung Cancer A549 Cells

Yao

Qian

Qin

2019

International Journal of Polymer Science

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Objective. To investigate the effect of Laminaria japonica polysaccharides (LJP) on the survival of non-small-cell lung cancer (NSCLC) A549 cells and its mechanism. Methods. In vitro: the cells were randomly divided into control group, LJP (5 mg/ml) group, LJP (10 mg/ml) group, and LJP (20 mg/ml) group. After corresponding treatment, the survival rate and the expression of proteins related to proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and signaling pathway were detected by CCK8 assay and Western blot, respectively. In vivo: a xenograft model was established to detect the tumor volume and mass and the expression of the above pathway proteins. Results. Compared with the control group, LJP decreased the survival rate of A549 cells (P<0.05), inhibited the protein expression of Ki67 and PCNA (P<0.05), downregulated the expression of Bcl-2 while upregulated the expression of Bax, cl-caspase-3, and cl-caspase-9 (P<0.05), upregulated the expression of E-cadherin, downregulated the expression of vascular endothelial growth factor (VEGF) and N-cadherin (P<0.05), and downregulated β-catenin, transcription factor-4 (TCF4), and c-Myc protein expression levels (P<0.05). In vivo: LJP decreased the volume and mass of the xenograft tumors and downregulated β-catenin, TCF4, and c-Myc protein expression levels compared with the control group (P<0.05). Conclusion. LJP can inhibit the survival of non-small-cell lung cancer A549 cells in vitro, and its mechanism is related to the inhibition of activation of β-catenin/TCF4 pathway activation.

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A Small Molecule Inhibitor of the β-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo

Cited by 50 publications

References 48 publications

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

Morphological Neurite Changes Induced by Porcupine Inhibition Are Rescued by Wnt Ligands

Effects of Laminaria Japonica Polysaccharides on the Survival of Non-Small-Cell Lung Cancer A549 Cells

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