Inhibiting the Cyclin-Dependent Kinase CDK5 Blocks Pancreatic Cancer Formation and Progression through the Suppression of Ras-Ral Signaling

被引：143

作者：

Feldmann, Georg ^{[2
]}

Mishra, Anjali ^{[1
]}

Hong, Seung-Mo ^{[2
]}

Bisht, Savita ^{[2
]}

Strock, Christopher J. ^{[1
]}

Ball, Douglas W. ^{[1
,3
]}

Goggins, Michael ^{[2
]}

Maitra, Anirban ^{[1
,2
]}

Nelkin, Barry D. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21231 USA

来源：

CANCER RESEARCH | 2010年 / 70卷 / 11期

关键词：

GTPASE-ACTIVATING PROTEIN; IN-VIVO; ALZHEIMERS-DISEASE; TUMOR INITIATION; CELLS; TARGET; GROWTH; PHOSPHORYLATION; MECHANISM; ROLES;

D O I：

10.1158/0008-5472.CAN-09-1107

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. Cancer Res; 70(11); 4460-9. (C) 2010 AACR.

引用

页码：4460 / 4469

页数：10

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