Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5

// Prisca Exertier 1,2 , Sophie Javerzat 1,2 , Baigang Wang 3,8 , Melanie Franco 1,2 , John Herbert 4 , Natalia Platonova 1,2 , Marie Winandy 5 , Nadege Pujol 1,2 , Olivier Nivelles 6 , Sandra Ormenese 7 , Virginie Godard 1,2 , Jurgen Becker 8 , Roy Bicknell 4 , Raphael Pineau 9 , Jorg Wilting 8* , Andreas Bikfalvi 1,2* , Martin Hagedorn 1,2* 1 Univ. Bordeaux, LAMC, UMR 1029, F-33405 Talence, France 2 INSERM, LAMC, UMR 1029, F-33405 Talence, France 3 Ruhr-Universitat Bochum, Medizinische Fakultat; 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, Universite de Liege, Belgium 6 GIGA, Unite de Biologie Moleculaire et Genie Genetique, Tour B34, Universite de Liege, Belgium 7 GIGA, Imaging and Flow Cytometry Facility, Tour B34, Universite de Liege, Belgium 8 Zentrum Anatomie, Abteilung Anatomie und Zellbiologie, Georg-August-Universitat Goettingen, Germany 9 Animalerie mutualisee, University of Bordeaux I, Talence, France * Co-PIs Correspondence: Martin Hagedorn, email: // Keywords : Angiogenesis, Eg5 kinesin, Mklp2 kinesin, VEGF, ispinesib Received : October 11, 2013 Accepted : October 24, 2013 Published : October 26, 2013 Abstract 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.