The OGF-OGFr axis utilizes the p21 pathway to restrict progression of human pancreatic cancer.

Abstract

BACKGROUND:

Pancreatic cancer is the 4th leading cause of death from cancer in the U.S. The opioid growth factor (OGF; [Met5]-enkephalin) and the OGF receptor form an inhibitory growth regulatory system involved in the pathogenesis and treatment of pancreatic cancer. The OGF-OGFr axis influences the G0/G1 phase of the cell cycle. In this investigation, we elucidate the pathway of OGF in the cell cycle.

RESULTS:

Using BxPC-3 cells, OGF decreased phosphorylation of retinoblastoma (Rb) protein without changing total Rb. This change was correlated with reduced cyclin-dependent kinase protein (Cdk) 2 kinase activity, but not total Cdk2. OGF treatment increased cyclin-dependent kinase inhibitor (CKI) p21 protein expression in comparison to controls, as well levels of p21 complexed with Cdk2. Naloxone abolished the increased expression of p21 protein by OGF, suggesting a receptor-mediated activity. p21 specific siRNAs blocked OGF's repressive action on proliferation in BxPC-3, PANC-1, and Capan-2 cells; cells transfected with negative control siRNA had no alteration in p21 expression, and therefore were inhibited by OGF.

CONCLUSION:

These data are the first to reveal that the target of cell proliferative inhibitory action of OGF in human pancreatic cancer is a p21 CKI pathway, expanding strategies for diagnosis and treatment of these neoplasias.

• Authors: Fan Cheng, Patricia J McLaughlin, Michael F Verderame, Ian S Zagon
• Journal: Molecular cancer (Mol Cancer) Vol. 7 Pg. 5 (Jan 11 2008) ISSN: 1476-4598 [Electronic] England
• PMID: 18190706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• RNA, Small Interfering
• Receptors, Opioid
• Retinoblastoma Protein
• methionine-enkephalin receptor
• Enkephalin, Methionine
• enkephalin-Met, Arg(6)-Phe(7)-
• Cyclin-Dependent Kinase 2

Topics

• Blotting, Western
• Cell Cycle (physiology)
• Cell Line, Tumor
• Cell Proliferation
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Disease Progression
• Enkephalin, Methionine (analogs & derivatives, metabolism)
• Flow Cytometry
• Humans
• Pancreatic Neoplasms (metabolism)
• RNA, Small Interfering
• Receptors, Opioid (genetics, metabolism)
• Retinoblastoma Protein (metabolism)
• Signal Transduction (physiology)
• Transfection