title: Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis.
abstract: Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Henriette
authors.initials: H
authors.lastname: Merk
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Siwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
authors.affiliation: Department of Pharmacy, Pharmaceutical Chemistry, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Department of Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.affiliation: Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.|University of Münster, Faculty of Medicine, 48149 Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Department of Pharmacy, Pharmaceutical Chemistry, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Liebl
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020533:Angiogenesis Inhibitors; D051880:Receptors, Notch; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse
keywords: Cdk5; Notch; angiogenesis; cancer