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

S. Camus, C. Quevedo, S. Menéndez, I. Paramonov, P. F.W. Stouten, R. A.J. Janssen, S. Rueb, S. He, B. E. Snaar-Jagalska, L. Laricchia-Robbio, Juan Carlos Izpisua Belmonte*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4333-4342
Number of pages10
JournalOncogene
Volume31
Issue number39
DOIs
StatePublished - Sep 27 2012

Keywords

  • PhK
  • angiogenesis
  • cancer
  • phosphorylase kinase
  • zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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