The Wnt/β-Catenin Signaling Pathway as a Target in Drug Discovery

Takahashi-Yanaga, Fumi; Sasaguri, Toshiyuki

doi:10.1254/jphs.cr0070024

Cited by 131 publications

(93 citation statements)

References 100 publications

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“…15,16 In our previous study, we demonstrated that b-catenin-targeting cancer therapy was effective in inhibiting tumor cell growth. 4 However, suppression of b-catenin may cause unexpected changes in the pathophysiology of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Gene silencing of β‐catenin in melanoma cells retards their growth but promotes the formation of pulmonary metastasis in mice

Takahashi

Nishikawa

Suehara

et al. 2008

Intl Journal of Cancer

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Altered expression of b-catenin, a key component of the Wnt signaling pathway, is involved in a variety of cancers because increased levels of b-catenin protein are frequently associated with enhanced cellular proliferation. Although our previous study demonstrated that gene silencing of b-catenin in melanoma B16-BL6 cells by plasmid DNA (pDNA) expressing short-hairpin RNA targeting the gene (pshb-catenin) markedly suppressed their growth in vivo, gene silencing of b-catenin could promote tumor metastasis by the rearranging cell adhesion complex. In this study, we investigated how silencing of b-catenin affects metastatic aspects of melanoma cells. Transfection of B16-BL6 cells with pshb-catenin significantly reduced the amount of cadherin protein, a cell adhesion molecule binding to b-catenin, with little change in its mRNA level. Cadherin-derived fragments were detected in culture media of B16-BL6 cells transfected with pshb-catenin, suggesting that cadherin is shed from the cell surface when the expression of b-catenin is reduced. The mobility of B16-BL6 cells transfected with pshb-catenin was greater than that of cells transfected with any of the control pDNAs. B16-BL6 cells stably transfected with pshb-catenin (B16/pshb-catenin) formed less or an equal number of tumor nodules in the lung than cells stably transfected with other plasmids when injected into mice via the tail vein. However, when subcutaneously inoculated, B16/pshb-catenin cells formed more nodules in the lung than the other stably transfected cells. These results raise concerns about the gene silencing of b-catenin for inhibiting tumor growth, because it promotes tumor metastasis by reducing the amount of cadherin in tumor cells. ' 2008 Wiley-Liss, Inc.Key words: b-catenin; cadherin; RNA interference; pulmonary metastasis; melanoma b-catenin is a key component of the Wnt signaling pathway, which transmits proliferative and survival signals to cells. 1 Aberrant Wnt signaling, including the stabilization and nuclear translocation of b-catenin, has been observed in various types of cancers, such as colon, lung, skin, breast, liver and pancreas cancers. 2 Nuclear translocation of b-catenin is followed by its cooperation with the T cell factor/lymphocyte-enhancer binding factor family and activation of the expression of genes related to cell proliferation and survival. Previous studies have shown that b-catenin plays an important role as an oncogene to promote tumor cell growth. 2,3 These lines of evidence support cancer therapy based on the suppression of b-catenin expression. In our previous study, we demonstrated that delivery of plasmid DNA (pDNA) expressing short-hairpin RNA (shRNA) targeting b-catenin (pshb-catenin) or hypoxia inducible factor-1a (HIF-1a; pshHIF-1a) to a murine melanoma B16-BL6 (B16) tumor could suppress the corresponding target gene expression. 4 Moreover, suppression of b-catenin expression in B16 tumor inhibited the tumor growth. To our surprise, however, we also noticed that the lungs of mice that had received intratumor...

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Section: Discussionmentioning

confidence: 99%

Gene silencing of β‐catenin in melanoma cells retards their growth but promotes the formation of pulmonary metastasis in mice

Takahashi

Nishikawa

Suehara

et al. 2008

Intl Journal of Cancer

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“…Prior to phosphorylation by GSK3β, priming phosphorylation of serine 45 on β-catenin by casein kinase 1 (CK1) is required, where CK1 is bound to axin [8]. Concurrently, transcriptional activity of TCF is inhibited by corepressor Groucho [9]. Upon binding of the Wnt ligand to the FZD membrane receptor protein and low-density lipoprotein receptor-related proteins (LRP-5/6), the canonical Wnt signalling pathway is activated ( Figure 1).…”

Section: Canonical Wnt Signalling Pathwaymentioning

confidence: 99%

Secreted frizzled related proteins: Implications in cancers

Surana

Sikka

Cai

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

103

114

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“…As a specific example, several cancers, including the majority of colon adenocarcinomas, arise due to gain-offunction mutations in the canonical Wnt signaling pathway. Pharmacological inhibitors of Wnt pathway are being actively developed in cancer medicine and it is possible that these may also find a role in enhancing remyelination by inhibiting Wnt signaling in CNS precursors and normalizing the kinetics of myelin regeneration [81,82].…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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The Wnt/β-Catenin Signaling Pathway as a Target in Drug Discovery

Cited by 131 publications

References 100 publications

Gene silencing of β‐catenin in melanoma cells retards their growth but promotes the formation of pulmonary metastasis in mice

Gene silencing of β‐catenin in melanoma cells retards their growth but promotes the formation of pulmonary metastasis in mice

Secreted frizzled related proteins: Implications in cancers

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

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