β-catenin signaling and cancer

Morin, Patrice J.

doi:10.1002/(sici)1521-1878(199912)22:1<1021::aid-bies6>3.0.co;2-p

Cited by 822 publications

(595 citation statements)

References 75 publications

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“…Theoretically, translocation of b-catenin to the nucleus leads to its association with TCFs and results in regulated transactivation of genes containing the LEF-1/TCF-4 binding sequence near their promoter, such as cyclin D1 (Morin, 1999;Shtutman et al, 1999;Lin et al, 2000). This theory is supported by our finding that the loss of E-cadherin in SKOV-3 cells resulted in increased activation of the TCF promoter-reporter construct, and was associated with increased levels of cyclin D1.…”

Section: Regulation Of Pten Levels By Cell Density and E-cadherin-cadsupporting

confidence: 53%

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

2011

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E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing b-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear b-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear b-catenin signaling by inactivating glycogen synthase kinase-3b indicating cross-talk between the PI3K/Akt and b-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via b-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing b-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification.

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Section: Regulation Of Pten Levels By Cell Density and E-cadherin-cadsupporting

confidence: 53%

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

2011

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“…12,16,20,22,56 Sodium butyrate, a differentiating agent known to induce growth arrest and/or maturation of colonic carcinoma cell lines, 35,38 -42 has been shown by us to modulate the BCT/Wnt pathway. 44 SW620 and HCT-116 colon cancer cells differ significantly in their physiologic response to butyrate 35,39 -42,44 and in the characteristics of their activated Wnt pathway.…”

Section: Discussionmentioning

confidence: 99%

Cell type‐ and promoter‐dependent modulation of the Wnt signaling pathway by sodium butyrate

Bordonaro

Lazarova

Augenlicht

et al. 2001

Intl Journal of Cancer

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The Wnt signaling pathway modulates the transcription of genes linked to proliferation, differentiation and tumor progression. ␤-Catenin-Tcf (BCT)-dependent Wnt signaling is influenced by the short-chain fatty acid sodium butyrate, which induces growth arrest and/or maturation of colonic carcinoma cells. We have compared the effects of sodium butyrate on BCT-dependent signaling in 2 colon carcinoma cell lines that differ in their physiologic response to butyrate, with SW620 cells responding to butyrate by undergoing terminal differentiation and apoptosis, and HCT-116 cells undergoing reversible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway activation, with adenomatous polyposis coli (APC) mutant SW620 cells having high levels of BCT complexes and APC wild-type HCT-116 cells having mutant ␤-catenin, low levels of BCT complexes and correspondingly higher levels of free Tcf. We have demonstrated that in SW620 cells, butyrate downregulates BCT-dependent expression of the Tcf-TK, matrilysin and cyclin D1 promoters, whereas in HCT-116 cells, butyrate upregulates expression of these promoters. Cotransfection with expression vectors that interfere with the Wnt pathway suggests that butyrate enhances BCT complex-DNA binding. Butyrate reduces the expression of Tcf4 in HCT-116 cells, consistent with the induction by butyrate of Tcf-repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT-116 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyrate.

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“…Disruption of xCT promotes b-catenin translocation to plasma membrane b-Catenin has two distinct functions, namely, maintaining cell-to-cell adhesion and mediating the Wnt/ b-catenin signaling pathway, which are largely determined by its subcellular location (Peifer, 1997;Morin, 1999;Peifer and Polakis, 2000). Considering the role of b-catenin in cell adhesion and the observation that CCA was enhanced by disruption of xCT, we applied immunofluorescent staining to detect the subcellular distribution of b-catenin.…”

Section: Disruption Of Xct Upregulates Caveolin-1mentioning

confidence: 99%

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

et al. 2008

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xCT, the functional subunit of the cystine/glutamate transporter xc-system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role of xCT in tumor metastasis remains largely unknown. In this study, both xCT þ / þ and xCT À/À melanocytes were used to evaluate the role of xCT in adhesion. xCT activity was suppressed by an inhibitor, sulfasalazine (SASP), or by xCT siRNA in an esophageal cancer cell line, KYSE150. We found that disruption of xCT enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and b-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of b-catenin transcriptional activity. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation. These results first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy.

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β-catenin signaling and cancer

Cited by 822 publications

References 75 publications

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

Cell type‐ and promoter‐dependent modulation of the Wnt signaling pathway by sodium butyrate

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

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