Identification of phosphorylase kinase as a novel therapeutic target through high-throughput screening for anti-angiogenesis compounds in zebrafish
| Autor: | S. Rueb, Pieter F. W. Stouten, Celia Quevedo, Shuning He, Leopoldo Laricchia-Robbio, Ida Paramonov, J. C. Izpisua Belmonte, Richard A.J. Janssen, Sergio Menendez, Suzanne Camus, B. E. Snaar-Jagalska |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Phosphorylase Kinase Angiogenesis High-throughput screening Drug Evaluation Preclinical Gene Dosage Angiogenesis Inhibitors Molecular oncology Cell Line Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine Neoplasms Genetics Animals Humans Molecular Targeted Therapy Phosphorylase kinase Molecular Biology Zebrafish 030304 developmental biology 0303 health sciences Neovascularization Pathologic biology Kinase Endothelial Cells Cell cycle biology.organism_classification Molecular biology High-Throughput Screening Assays Up-Regulation 3. Good health Tumor progression 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | Oncogene; Vol 31 Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2011.594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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