Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis
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Henriette Merk1, Siwei Zhang1, Thorsten Lehr2, Christoph Müller3, Melanie Ulrich1, James A. Bibb4, Ralf H. Adams5,6, Franz Bracher3, Stefan Zahler1, Angelika M. Vollmar1, Johanna Liebl1
1Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany
2Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany
3Department of Pharmacy, Pharmaceutical Chemistry, Ludwig-Maximilians-University, 81377 Munich, Germany
4Department of Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390–9070, USA
5Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany
6University of Münster, Faculty of Medicine, 48149 Münster, Germany
Johanna Liebl, e-mail: [email protected]
Keywords: Cdk5, angiogenesis, cancer, Notch
Received: June 24, 2015 Accepted: December 29, 2015 Published: January 08, 2016
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.
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