Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5
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Prisca Exertier1,2, Sophie Javerzat1,2, Baigang Wang3,8, Mélanie Franco1,2, John Herbert4, Natalia Platonova1,2, Marie Winandy5, Nadège Pujol1,2, Olivier Nivelles6, Sandra Ormenese7, Virginie Godard1,2, Jürgen Becker8, Roy Bicknell4, Raphael Pineau9, Jörg Wilting8*, Andreas Bikfalvi1,2*, Martin Hagedorn1,2*
1 Univ. Bordeaux, LAMC, UMR 1029, F-33405 Talence, France
2 INSERM, LAMC, UMR 1029, F-33405 Talence, France
3 Ruhr-Universität Bochum, Medizinische Fakultät; Abt. f. Anatomie und Embryologie, D-44780 Bochum, Germany
4 Molecular Angiogenesis Group, Institute of Biomedical Research, Univ Birmingham, Medical School, Edgbaston, Birmingham, UK
5 GIGA, Zebrafish Facility, Tour B34, Université de Liège, Belgium
6 GIGA, Unité de Biologie Moléculaire et Génie Génétique, Tour B34, Université de Liège, Belgium
7 GIGA, Imaging and Flow Cytometry Facility, Tour B34, Université de Liege, Belgium
8 Zentrum Anatomie, Abteilung Anatomie und Zellbiologie, Georg-August-Universität Goettingen, Germany
9 Animalerie mutualisée, University of Bordeaux I, Talence, France
Martin Hagedorn, email:
Keywords: Angiogenesis, Eg5 kinesin, Mklp2 kinesin, VEGF, ispinesib
Received: October 11, 2013 Accepted: October 24, 2013 Published: October 26, 2013
Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.
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