Purpose: Investigate the expression and function of CDK5 and its co-activators p35 and p39 in pancreatic cancer Experimental Design: Determine the genetic and biochemical cause of CDK5 hyperactivity in 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, while greater 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 cells (HPNE) expressing a mutant form of K-Ras (G12D) compared to 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 MEK, PI3K 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.
- Received September 7, 2010.
- Revision received July 18, 2011.
- Accepted July 24, 2011.
- Copyright © 2011, American Association for Cancer Research.