PMID: 27027353 RLIMS-P 1 eFIP 0 miRTex 0 eGARD 0 Issue Report
Title
| 1. | Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1α: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma. |
Abstract
| 2. | We recently introduced CDK5 as target in HCC, regulating DNA damage response. |
| 3. | Based on this and on our previous knowledge about vascular effects of CDK5, we investigated the role of CDK5 in angiogenesis in HCC, one of the most vascularized tumors. |
| 4. | We put a special focus on the transcription factor HIF-1α, a master regulator of tumor angiogenesis.The interaction of CDK5 with HIF-1α was tested by Western blot, PCR, reporter gene assay, immunohistochemistry, kinase assay, co-immunoprecipitation, mass spectrometry, and mutation studies. |
| 5. | In vivo, different murine HCC models, were either induced by diethylnitrosamine or subcutaneous injection of HUH7 or HepG2 cells. |
| 6. | The correlation of vascular density and CDK5 was assessed by immunostaining of a microarray of liver tissues from HCC patients.Inhibition of CDK5 in endothelial or HCC cells reduced HIF-1α levels in vitro and in vivo, and transcription of HIF-1α target genes (VEGFA, VEGFR1, EphrinA1). |
| 7. | Mass spectrometry and site directed mutagenesis revealed a stabilizing phosphorylation of HIF-1α at Ser687 by CDK5. |
| 8. | Vascular density was decreased in murine HCC models by CDK5 inhibition.In conclusion, inhibiting CDK5 is a multi-modal systemic approach to treat HCC, hitting angiogenesis, as well as the tumor cells themselves. |
Loading...
Loading data