Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling.
Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling.
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DOI：
10.1158/0008-5472.can-09-1107
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发表时间：
2010-06-01
期刊：
影响因子：
11.2
通讯作者：
Nelkin BD
中科院分区：
文献类型：
--
作者：
Feldmann G;Mishra A;Hong SM;Bisht S;Strock CJ;Ball DW;Goggins M;Maitra A;Nelkin BD
细胞周期蛋白依赖性激酶5（CDK5），一种在迁移中起作用的神经元激酶，已被发现在一些人类癌症中被激活，其中它与促进转移有关。在这项研究中，我们研究了CDK5在胰腺癌中的作用，其中转移性疾病在诊断时最常见。CDK5在胰腺癌细胞中具有广泛的活性。功能性消融显著抑制体外侵袭、迁移和锚定非依赖性生长，以及体内原位肿瘤形成和全身转移。CDK5阻断通过其关键效应物RalA和RalB导致Ras信号传导的深度抑制。相反，恢复Ral功能挽救了胰腺癌细胞中CDK5抑制的效果。我们的发现将CDK5确定为降解胰腺癌中Ras信号传导的易降解靶点。
Cyclin-dependent kinase 5 (CDK5), a neuronal kinase that functions in migration, has been found to be activated in some human cancers where it has been implicated in promoting metastasis. In this study, we investigated the role of CDK5 in pancreatic cancers where metastatic disease is most common at diagnosis. CDK5 was widely active in pancreatic cancer cells. Functional ablation significantly inhibited invasion, migration and anchorage-independent growth in vitro, and orthotopic tumor formation and systemic metastases in vivo. CDK5 blockade resulted in profound inhibition of Ras signaling through its critical effectors RalA and RalB. Conversely, restoring Ral function rescued the effects of CDK5 inhibition in pancreatic cancer cells. Our findings identify CDK5 as a pharmacologically tractable target to degrade Ras signaling in pancreatic cancer.