title: Targeting cyclin dependent kinase 5 in hepatocellular carcinoma--A novel therapeutic approach.
abstract: OBJECTIVE
  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.
authors: Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany.
authors: Sandra M
authors: SM
authors: Ehrlich
authors: Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany.
authors: Johanna
authors: J
authors: Liebl
authors: Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany.
authors: Maximilian A
authors: MA
authors: Ardelt
authors: Clinical Pharmacy, Saarland University, Saarbrücken, Germany.
authors: Thorsten
authors: T
authors: Lehr
authors: Department of Internal Medicine II, Liver Center Munich®, Hospital of the Ludwig Maximilians University of Munich, Campus Grosshadern, Munich, Germany.
authors: Enrico N
authors: EN
authors: De Toni
authors: Institute of Pathology, Ludwig Maximilians University of Munich, Munich, Germany.
authors: Doris
authors: D
authors: Mayr
authors: Institute of Pathology, Ludwig Maximilians University of Munich, Munich, Germany.
authors: Lydia
authors: L
authors: Brandl
authors: Institute of Pathology, Ludwig Maximilians University of Munich, Munich, Germany.
authors: Thomas
authors: T
authors: Kirchner
authors: Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany.
authors: Stefan
authors: S
authors: Zahler
authors: Department of Internal Medicine II, Liver Center Munich®, Hospital of the Ludwig Maximilians University of Munich, Campus Grosshadern, Munich, Germany.
authors: Alexander L
authors: AL
authors: Gerbes
authors: Department of Pharmacy, Pharmaceutical Biology, Ludwig Maximilians University of Munich, Munich, Germany. Electronic address: angelika.vollmar@cup.uni-muenchen.de.
authors: Angelika M
authors: AM
authors: Vollmar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D011687:Purines / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000235:genetics*; D000077546:Roscovitine; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; D012334:RNA, Neoplasm; D000077546:Roscovitine; D000077146:Irinotecan; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D002166:Camptothecin
keywords: Cdk5; Chemosensitization; DNA damage; HCC; Roscovitine; Sn38