Targeting cyclin dependent kinase 5 in hepatocellular carcinoma--A novel therapeutic approach.

Autor: Ehrlich SM; Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany., Liebl J; Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany., Ardelt MA; Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany., Lehr T; Clinical Pharmacy, Saarland University, Saarbrücken, Germany., De Toni EN; Department of Internal Medicine II, Liver Center Munich®, Hospital of the Ludwig Maximilians University of Munich, Campus Grosshadern, Munich, Germany., Mayr D; Institute of Pathology, Ludwig Maximilians University of Munich, Munich, Germany., Brandl L; Institute of Pathology, Ludwig Maximilians University of Munich, Munich, Germany., Kirchner T; Institute of Pathology, Ludwig Maximilians University of Munich, Munich, Germany., Zahler S; Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany., Gerbes AL; Department of Internal Medicine II, Liver Center Munich®, Hospital of the Ludwig Maximilians University of Munich, Campus Grosshadern, Munich, Germany., Vollmar AM; Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany. Electronic address: angelika.vollmar@cup.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2015 Jul; Vol. 63 (1), pp. 102-13. Date of Electronic Publication: 2015 Feb 07.
DOI: 10.1016/j.jhep.2015.01.031
Abstrakt: Background & Aims: For a long time cyclin dependent kinase 5 (Cdk5) was thought to be exclusively important in neuronal cells. However, increasing evidence recently suggests a function of Cdk5 in cancer progression. In this study, we examined the role of Cdk5 and its therapeutic accessibility in hepatocellular carcinoma (HCC), a highly chemoresistant cancer with poor prognosis and paramount clinical importance in order to develop novel targeted therapies for systemic treatment.
Methods: Expression and activity of Cdk5 was analyzed in a human HCC tissue microarray, human patient samples and HCC cell lines. To characterize Cdk5 functions and signaling pathways in HCC, we applied genetic downregulation and pharmacologic inhibition in various approaches including cell based assays and mouse xenograft models.
Results: Expression and activity of Cdk5 was increased in human HCC tissues as compared to normal liver tissues. Functional ablation of Cdk5 significantly decreased HCC cell proliferation and clonogenic survival. Moreover, genetic and pharmacological inhibition of Cdk5 showed in vivo efficacy in HCC xenograft mouse models. Investigating the mechanisms behind these functional effects revealed that Cdk5 is most active in the nucleus of cells in G2/M phase. Cdk5 regulates DNA damage response by phosphorylating ataxia telangiectasia mutated (ATM) kinase and thereby influencing its downstream cascade. Consequently, combination of Cdk5 inhibition with DNA-damage-inducing chemotherapeutics synergistically inhibited HCC tumor progression in vitro and in vivo.
Conclusions: In summary, we introduce Cdk5 as a novel drugable target for HCC treatment and suggest the combination of Cdk5 inhibition and DNA damaging agents as a novel therapeutic approach.
(Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: