The role of Cdk5 as target in hepatocellular carcinoma

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Cyclin dependent kinase 5 (Cdk5), which is not directly involved in cell cycle control, has emerged as a crucial regulator in the developing nervous system. Recently, solitary studies suggested a role of Cdk5 in tumor cell survival as well as in angiogenesis. In fact, based on our preliminary data we propose Cdk5 as an attractive target for HCC systemic therapy and anti-angiogenic approach. So far, we have shown that Cdk5 as well as p35 are upregulated in human HCC. Pharmacological or genetic inhibition of Cdk5 inhibits HCC survival, sensitizes HCC for TRAIL induced apoptosis and abrogates migration in vitro. Cdk5-inhibition reduces tumor growth and vascularization in vivo. We now aim at a detailed characterization of the molecular basis of 1) the role of Cdk5 for growth and survival of HCC cells as well as the chemosensitizing effects via inhibition of Cdk5 and 2) the impact of Cdk5 on the motility of HCC cells as well as on angiogenesis in HCC. Besides roscovitine (Seliciclib®) which has already been used in clinical phase IIb trials, we have access to novel inhibitors of Cdk5. Thus this project aims to have a translational, therapeutically relevant outcome in addition to the basic cell biological gain of knowledge.