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Kallistatin antagonizes Wnt/β-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6

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Abstract

Kallistatin, a plasma protein, exerts pleiotropic effects in inhibiting angiogenesis, inflammation and tumor growth. Canonical Wnt signaling is the primary pathway for oncogenesis in the mammary gland. In this study, we demonstrate that kallistatin bound to the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), thus, blocking Wnt/β-catenin signaling and Wnt-mediated growth and migration in MDA-MB-231 breast cancer cells. Kallistatin inhibited Wnt3a-induced proliferation, migration, and invasion of cultured breast cancer cells. Moreover, kallistatin was bound to LRP6 in breast cancer cells, as identified by immunoprecipitation followed by western blot. Kallistatin suppressed Wnt3a-mediated phosphorylation of LRP6 and glycogen synthase kinase-3β, and the elevation of cytosolic β-catenin levels. Furthermore, kallistatin antagonized Wnt3a-induced expression of c-Myc, cyclin D1, and vascular endothelial growth factor. These findings indicate a novel role of kallistatin in preventing breast tumor growth and mobility by direct interaction with LRP6, leading to blockade of the canonical Wnt signaling pathway.

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Acknowledgments

This research was supported by the National Institutes of Health Grants HL29397 and HL44083.

Conflict of interest

The authors have no conflicts of interest to disclosure.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA

    Jingmei Zhang, Zhirong Yang, Pengfei Li, Lee Chao & Julie Chao

  2. Department of Biology, Charleston Southern University, 9200 University Boulevard, Charleston, SC, 29406, USA

    Grant Bledsoe

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  1. Jingmei Zhang
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  2. Zhirong Yang
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  3. Pengfei Li
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  4. Grant Bledsoe
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  5. Lee Chao
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  6. Julie Chao
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Correspondence to Julie Chao.

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Zhang, J., Yang, Z., Li, P. et al. Kallistatin antagonizes Wnt/β-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6. Mol Cell Biochem 379, 295–301 (2013). https://doi.org/10.1007/s11010-013-1654-2

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  • DOI: https://doi.org/10.1007/s11010-013-1654-2

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