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Identification of phosphorylase kinase as a novel therapeutic target through high-throughput screening for anti-angiogenesis compounds in zebrafish

Oncogene volume 31, pages 4333–4342 (2012)Cite this article

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Abstract

Angiogenesis is essential for development and tumor progression. With the aim of identifying new compound inhibitors of the angiogenesis process, we used an established enhanced green fluorescent protein-transgenic zebrafish line to develop an automated assay that enables high-throughput screening of compound libraries in a whole-organism setting. Using this system, we have identified novel kinase inhibitor compounds that show anti-angiogenic properties in both zebrafish in-vivo system and in human endothelial cell in-vitro angiogenesis models. Furthermore, we have determined the kinase target of these compounds and have identified and validated a previously uncharacterized involvement of phosphorylase kinase subunit G1 (PhKG1) in angiogenesis in vivo. In addition, we have found that PhKG1 is upregulated in human tumor samples and that aberrations in gene copy number of PhK subunits are a common feature of human tumors. Our results provide a novel insight into the angiogenesis process, as well as identify new potential targets for anti-angiogenic therapies.

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Acknowledgements

We would like to thank Cornel Catana of Galapagos for molecular modeling efforts and acknowledge the support and intellectual contribution of the Scientific Director of Biobide, Carles Callol. This project was financially supported by the European Community under the FP7 ZF-Cancer project (HEALTH-F2-2008-201439), MICINN and Fundacion Cellex.

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Authors and Affiliations

  1. Center for Regenerative Medicine in Barcelona, Barcelona, Spain

    S Camus, S Menéndez, I Paramonov, L Laricchia-Robbio & J C Izpisua Belmonte

  2. Biobide SL, San Sebastián, Spain

    C Quevedo

  3. Galapagos, NV, Mechelen, Belgium

    P F W Stouten

  4. Galapagos, BV, Leiden, The Netherlands

    R A J Janssen

  5. Institute of Biology, Leiden University, Leiden, The Netherlands

    S Rueb, S He & B E Snaar-Jagalska

  6. Salk Institute for Biological Studies, La Jolla, CA, USA

    J C Izpisua Belmonte

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  1. S Camus
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  2. C Quevedo
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  3. S Menéndez
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Correspondence to J C Izpisua Belmonte.

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Camus, S., Quevedo, C., Menéndez, S. et al. Identification of phosphorylase kinase as a novel therapeutic target through high-throughput screening for anti-angiogenesis compounds in zebrafish. Oncogene 31, 4333–4342 (2012). https://doi.org/10.1038/onc.2011.594

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  • DOI: https://doi.org/10.1038/onc.2011.594

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