Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.

Abstract

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.

• Authors: John P Eggers, Paul M Grandgenett, Eric C Collisson, Michelle E Lewallen, Jarrod Tremayne, Pankaj K Singh, Benjamin J Swanson, Judy M Andersen, Thomas C Caffrey, Robin R High, Michel Ouellette, Michael A Hollingsworth
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 19 Pg. 6140-50 (Oct 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21825040 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR

Chemical References

• Adaptor Proteins, Signal Transducing
• CDCA5 protein, human
• Cdk5 activator p39
• Cell Cycle Proteins
• Nerve Tissue Proteins
• Purines
• Roscovitine
• Cyclin-Dependent Kinase 5

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adenocarcinoma
• Carcinoma, Pancreatic Ductal (enzymology, pathology)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 5 (antagonists & inhibitors, genetics, metabolism)
• Disease Progression
• Enzyme Activation (genetics)
• Gene Amplification
• Genes, ras
• Humans
• Mutation
• Neoplasm Invasiveness
• Nerve Tissue Proteins (metabolism)
• Pancreatic Neoplasms (genetics, metabolism)
• Purines (pharmacology)
• Roscovitine