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Endostatin is a potential inhibitor of Wnt signaling
Jun-ichi Hanai1, Joachim Gloy, S Ananth Karumanchi
1Department of Medicine and Center for Study of the Tumor Microenvironment, Division of Nephrology, Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Abstract:
Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. To gain insight into ES-mediated signaling, we studied the effects of ES RNA on Xenopus embryogenesis and observed developmental abnormalities consistent with impaired Wnt signaling. ES RNA blocked the axis duplication induced by beta-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and "stabilized" forms of beta-catenin, the latter suggesting that ES signaling does not involve glycogen synthase kinase 3. Moreover, ES uses a pathway independent of the Siah1 protein in targeting beta-catenin for proteasome-mediated degradation. ES failed to suppress the effects of T cell-specific factor (TCF)-VP16 (TVP), a constitutive downstream transcriptional activator that acts independently of beta-catenin. Importantly, these data were replicated in endothelial cells and also in the DLD-1 colon carcinoma cells with the mutated adenomatous polyposis coli protein. Finally, suppression of endothelial cell migration and inhibition of cell cycle by ES were reversed by TVP. Though high levels of ES were used in both the Xenopus and endothelial cell studies and the effects on beta-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote beta-catenin degradation.
Insights
Endostatin (ES), a collagen fragment, may impact Wnt signaling by promoting beta-catenin degradation. This antiangiogenic factor
Area of Science:
- Molecular Biology
- Developmental Biology
- Oncology
Background:
- Endostatin (ES), a collagen XVIII fragment, exhibits antiangiogenic properties.
- The precise signaling pathways modulated by ES remain incompletely understood.
- Wnt signaling is crucial for embryonic development and is often dysregulated in cancer.
Purpose of the Study:
- To investigate the molecular mechanisms underlying Endostatin-mediated signaling.
- To determine if ES influences Wnt signaling pathways.
- To explore the potential impact of ES on beta-catenin stability and degradation.
Main Methods:
- Xenopus embryogenesis assays with ES RNA.
- Analysis of Wnt-dependent gene expression and beta-catenin levels.
- Studies in endothelial and colon carcinoma cells (DLD-1).
- Assessment of TCF-VP16 (TVP) effects on ES-induced signaling.
Main Results:
- ES RNA induced developmental abnormalities in Xenopus, suggesting impaired Wnt signaling.
- ES promoted the degradation of beta-catenin, independent of GSK3.
- ES-mediated beta-catenin degradation occurs via a Siah1-independent pathway.
- ES suppressed endothelial cell migration and cell cycle, effects reversible by TVP.
Conclusions:
- Endostatin may impinge on Wnt signaling at pharmacological concentrations by promoting beta-catenin degradation.
- ES affects key cellular processes like migration and cell cycle progression.
- These findings suggest a potential role for ES in modulating cellular behavior through Wnt pathway interference.