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Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription
1Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, 48109, USA.
Abstract:
Wnt signaling plays a critical role in development and oncogenesis. Although significant progress has been made in understanding the downstream signaling cascade of Wnt signaling, little is known regarding Wnt signaling modification of the cell death machinery. Given that numerous oncogenes transform cells by providing cell survival function, we hypothesized that Wnt signaling may inhibit apoptosis. Here, we report that cells expressing Wnt-1 were resistant to cancer therapy-mediated apoptosis. Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that Wnt-1-mediated cell survival was dependent on the activation of beta-catenin/T cell factor (Tcf) transcription. Inhibition of beta-catenin/Tcf transcription by expression of the dominant-negative mutant of Tcf-4 blocked Wnt-1-mediated cell survival and rendered cells sensitive to apoptotic stimuli. These results provide the first demonstration that Wnt-1 inhibits cancer therapy-mediated apoptosis and suggests that Wnt-1 may exhibit its oncogenic potential through a mechanism of anti-apoptosis.
Insights
Wnt-1 signaling prevents cancer cells from undergoing apoptosis triggered by chemotherapy. This Wnt-1 pathway, mediated by beta-catenin/T cell factor transcription, offers cancer cells survival advantages.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Wnt signaling is crucial in development and cancer, but its role in regulating apoptosis remains unclear.
- Many oncogenes promote cell survival, suggesting a potential link between Wnt signaling and apoptosis inhibition.
Purpose of the Study:
- To investigate the hypothesis that Wnt signaling inhibits apoptosis.
- To determine if Wnt-1 confers resistance to cancer therapy-induced cell death.
Main Methods:
- Cells expressing Wnt-1 were treated with chemotherapeutic drugs (vincristine, vinblastine).
- Assessed cytochrome c release and caspase-9 activation.
- Investigated the role of beta-catenin/T cell factor (Tcf) transcription using a dominant-negative Tcf-4 mutant.
Main Results:
- Wnt-1 expression rendered cells resistant to apoptosis induced by vincristine and vinblastine.
- Wnt-1 signaling inhibited cytochrome c release and caspase-9 activation.
- Wnt-1-mediated cell survival required beta-catenin/Tcf transcriptional activity; blocking this pathway restored apoptosis sensitivity.
Conclusions:
- Wnt-1 actively inhibits apoptosis triggered by cancer therapies.
- Wnt-1 may exert its oncogenic effects by promoting anti-apoptotic functions.
- Targeting the Wnt-1/beta-catenin/Tcf pathway could be a strategy to overcome therapy resistance in cancer.