抑制细胞周期蛋白依赖性激酶 CDK5 通过抑制 Ras-Ral 信号通路阻断胰腺癌的形成和进展。
Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling.
机构信息
Departments of Pathology, Oncology, and Medicine, and The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
出版信息
Cancer Res. 2010 Jun 1;70(11):4460-9. doi: 10.1158/0008-5472.CAN-09-1107. Epub 2010 May 18.
Abstract
Cyclin-dependent kinase 5 (CDK5), a neuronal kinase that functions in migration, has been found to be activated in some human cancers in which it has been implicated in promoting metastasis. In this study, we investigated the role of CDK5 in pancreatic cancers in which 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 the 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.
摘要
周期蛋白依赖性激酶 5（CDK5）是一种在神经元迁移中起作用的激酶，已在一些人类癌症中被发现被激活，这些癌症中 CDK5 被认为有助于促进转移。在这项研究中，我们研究了 CDK5 在胰腺癌中的作用，转移性疾病在胰腺癌中最常见于诊断时。CDK5 在胰腺癌细胞中广泛活跃。功能缺失显著抑制了体外侵袭、迁移和非锚定依赖性生长，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 信号的深度抑制。相反，恢复 Ral 功能挽救了 CDK5 抑制对胰腺癌细胞的作用。我们的研究结果确定 CDK5 是一种可药物治疗的靶点，可降解胰腺癌中的 Ras 信号。
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