Journal
CLINICAL CANCER RESEARCH
Volume 17, Issue 19, Pages 6140-6150Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-2288
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Funding
- NIH [R01CA57362, U01CA111294, P50 CA127297]
- National Cancer Institute (NCI) [CA09476]
- University of Nebraska
- NCI Cancer Center [P30CA36727]
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Purpose: To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression. Experimental Design: We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer. Results: Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K-Ras (G12D) that involves mitogen-activated protein/extracellular signal-regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels. Conclusion: These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells. Clin Cancer Res; 17(19); 6140-50. (C) 2011 AACR.
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