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

John P. Eggers, Paul M. Grandgenett, Eric C. Collisson, Michelle E. Lewallen, Jarrod Tremayne, Pankaj Singh, Benjamin J Swanson, Judy M. Andersen, Thomas C. Caffrey, Robin R. High, Michel M Ouellette, Michael A Hollingsworth

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6140-6150
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number19
DOIs
StatePublished - Oct 1 2011

Fingerprint

Cyclin-Dependent Kinase 5
Pancreatic Neoplasms
Nestin
Molecular Biology
Mitogen-Activated Protein Kinase 6
Adenocarcinoma
Phosphotransferases
Proteins
1-Phosphatidylinositol 4-Kinase
Pancreatic Ducts
Mitogens

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras. / Eggers, John P.; Grandgenett, Paul M.; Collisson, Eric C.; Lewallen, Michelle E.; Tremayne, Jarrod; Singh, Pankaj; Swanson, Benjamin J; Andersen, Judy M.; Caffrey, Thomas C.; High, Robin R.; Ouellette, Michel M; Hollingsworth, Michael A.

In: Clinical Cancer Research, Vol. 17, No. 19, 01.10.2011, p. 6140-6150.

Research output: Contribution to journalArticle

Eggers, John P. ; Grandgenett, Paul M. ; Collisson, Eric C. ; Lewallen, Michelle E. ; Tremayne, Jarrod ; Singh, Pankaj ; Swanson, Benjamin J ; Andersen, Judy M. ; Caffrey, Thomas C. ; High, Robin R. ; Ouellette, Michel M ; Hollingsworth, Michael A. / Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 19. pp. 6140-6150.
@article{5aff46d588fe492eb9d343c01be5b27f,
title = "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.",
author = "Eggers, {John P.} and Grandgenett, {Paul M.} and Collisson, {Eric C.} and Lewallen, {Michelle E.} and Jarrod Tremayne and Pankaj Singh and Swanson, {Benjamin J} and Andersen, {Judy M.} and Caffrey, {Thomas C.} and High, {Robin R.} and Ouellette, {Michel M} and Hollingsworth, {Michael A}",
year = "2011",
month = "10",
day = "1",
doi = "10.1158/1078-0432.CCR-10-2288",
language = "English (US)",
volume = "17",
pages = "6140--6150",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "19",

}

TY - JOUR

T1 - Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras

AU - Eggers, John P.

AU - Grandgenett, Paul M.

AU - Collisson, Eric C.

AU - Lewallen, Michelle E.

AU - Tremayne, Jarrod

AU - Singh, Pankaj

AU - Swanson, Benjamin J

AU - Andersen, Judy M.

AU - Caffrey, Thomas C.

AU - High, Robin R.

AU - Ouellette, Michel M

AU - Hollingsworth, Michael A

PY - 2011/10/1

Y1 - 2011/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80053542961&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053542961&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-10-2288

DO - 10.1158/1078-0432.CCR-10-2288

M3 - Article

VL - 17

SP - 6140

EP - 6150

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 19

ER -