Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling.
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.
Feldmann
Georg
G
Departments of Pathology, Oncology, and Medicine, and The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Mishra
Anjali
A
Hong
Seung-Mo
SM
Bisht
Savita
S
Strock
Christopher J
CJ
Ball
Douglas W
DW
Goggins
Michael
M
Maitra
Anirban
A
Nelkin
Barry D
BD
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D020725:ral GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C500695:CDCA5 protein, human; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt; C495905:CDK5 protein, human; D020725:ral GTP-Binding Proteins; D018631:ras Proteins