Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells.
We show here that cyclin-dependent kinase 5 (CDK5), a known regulator of migration in neuronal development, plays an important role in prostate cancer motility and metastasis. P35, an activator of CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined. Blocking of CDK5 activity with a dominant-negative CDK5 construct, small interfering RNA, or roscovitine resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Expression of a dominant-negative CDK5 in the highly metastatic Dunning AT6.3 prostate cancer cell line also greatly impaired invasive capacity. CDK5 activity was important for spontaneous metastasis in vivo; xenografts of AT6.3 cells expressing dominant-negative CDK5 had less than one-fourth the number of lung metastases exhibited by AT6.3 cells expressing the empty vector. These results show that CDK5 activity controls cell motility and metastatic potential in prostate cancer.
Strock
Christopher J
CJ
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
Park
Jong-In
JI
Nakakura
Eric K
EK
Bova
G Steven
GS
Isaacs
John T
JT
Ball
Douglas W
DW
Nelkin
Barry D
BD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002465:Cell Movement / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C500695:CDCA5 protein, human; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D051360:Cyclin-Dependent Kinase 5