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调控，已成为神经系统发育过程中的重要调节因子。最近，单独的研究表明，CDK5在肿瘤细胞存活和血管生成中发挥作用。事实上，基于我们的初步数据，我们建议将CDK5作为肝癌系统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在人肝细胞癌中表达上调。药物或遗传抑制CDK5可抑制肝细胞癌存活，使肝细胞癌对TRAIL诱导的细胞凋亡敏感，并抑制体外迁移。CDK5抑制减少了体内肿瘤的生长和血管形成。我们现在的目标是详细地描述1)CDK5对肝癌细胞生长和存活的作用以及通过抑制CDK5而产生的化疗增敏作用的分子基础；2)CDK5对肝癌细胞运动和肝细胞癌血管生成的影响。除了已经用于临床IIb期试验的罗斯科维汀(Seliclib®)外，我们还可以获得CDK5的新型抑制剂。因此，这个项目的目标是除了获得基本的细胞生物学知识外，还有翻译上的、治疗上相关的结果。

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.