The role of Cdk5 as target in hepatocellular carcinoma

细胞周期蛋白依赖性激酶5 （Cdk5）不直接参与细胞周期控制，但在发育中的神经系统中已成为一个重要的调节因子。最近，个别研究表明Cdk5在肿瘤细胞存活和血管生成中发挥作用。事实上，根据我们的初步数据，我们提出Cdk5作为HCC全身治疗和抗血管生成方法的一个有吸引力的靶点。到目前为止，我们已经证明Cdk5和p35在人类HCC中上调。药理或遗传抑制Cdk5抑制HCC存活，使HCC对TRAIL诱导的细胞凋亡敏感，并在体外消除迁移。抑制cdk5抑制肿瘤生长和体内血管化。我们现在的目标是详细描述以下分子基础：1)Cdk5在HCC细胞生长和存活中的作用，以及通过抑制Cdk5产生的化学增敏效应；2)Cdk5对HCC细胞运动和血管生成的影响。除了已经在临床IIb期试验中使用的罗斯科维汀（Seliciclib®），我们还获得了新的Cdk5抑制剂。因此，这个项目的目的是有一个翻译，治疗相关的结果，除了基本的细胞生物学知识的增益。

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.