TY - JOUR
T1 - Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling
AU - Feldmann, Georg
AU - Mishra, Anjali
AU - Hong, Seung Mo
AU - Bisht, Savita
AU - Strock, Christopher J.
AU - Ball, Douglas W.
AU - Goggins, Michael
AU - Maitra, Anirban
AU - Nelkin, Barry D.
PY - 2010/6/1
Y1 - 2010/6/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=77953149881&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-1107
DO - 10.1158/0008-5472.CAN-09-1107
M3 - Article
C2 - 20484029
AN - SCOPUS:77953149881
VL - 70
SP - 4460
EP - 4469
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -