Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids
Tianyi Zhang1, Fu-Ning Hsu2, Xiao-Jun Xie2
1Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637.
Abstract:
Deregulated Wnt signaling and altered lipid metabolism have been linked to obesity, diabetes, and various cancers, highlighting the importance of identifying inhibitors that can modulate Wnt signaling and aberrant lipid metabolism. We have established a Drosophila model with hyperactivated Wnt signaling caused by partial loss of axin, a key component of the Wnt cascade. The Axin mutant larvae are transparent and have severe adipocyte defects caused by up-regulation of β-catenin transcriptional activities. We demonstrate pharmacologic mitigation of these phenotypes in Axin mutants by identifying bortezomib and additional peptide boronic acids. We show that the suppressive effect of peptide boronic acids on hyperactive Wnt signaling is dependent on α-catenin; the rescue effect is completely abolished with the depletion of α-catenin in adipocytes. These results indicate that rather than targeting the canonical Wnt signaling pathway directly, pharmacologic modulation of β-catenin activity through α-catenin is a potentially attractive approach to attenuating Wnt signaling in vivo.
Insights
Researchers found that peptide boronic acids can mitigate Wnt signaling and adipocyte defects in a Drosophila model. This modulation of beta-catenin activity via alpha-catenin offers a novel therapeutic strategy for related diseases.
Area of Science:
- Molecular Biology
- Developmental Biology
- Pharmacology
Background:
- Aberrant Wnt signaling and lipid metabolism are implicated in obesity, diabetes, and cancer.
- Identifying therapeutic targets that modulate these pathways is crucial.
Purpose of the Study:
- To establish a Drosophila model of hyperactivated Wnt signaling.
- To identify pharmacologic agents that can mitigate Wnt signaling and associated phenotypes.
- To elucidate the mechanism of action for identified inhibitors.
Main Methods:
- Established a Drosophila model with hyperactivated Wnt signaling due to partial loss of axin.
- Screened for pharmacologic agents capable of rescuing phenotypes in Axin mutants.
- Investigated the role of alpha-catenin in mediating the effects of peptide boronic acids.
Main Results:
- Axin mutant larvae exhibited transparency and severe adipocyte defects due to upregulated beta-catenin.
- Bortezomib and peptide boronic acids were identified as effective in mitigating these phenotypes.
- The suppressive effect of peptide boronic acids on Wnt signaling was dependent on alpha-catenin.
Conclusions:
- Pharmacologic modulation of beta-catenin activity through alpha-catenin is a viable strategy for attenuating Wnt signaling in vivo.
- This approach offers a potential therapeutic avenue for diseases associated with Wnt pathway dysregulation and metabolic disorders.
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