Research

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

Fan Cheng¹ , Patricia J McLaughlin¹ , Michael F Verderame² and Ian S Zagon¹

¹  Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA

²  Department of Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA

author email corresponding author email

Molecular Cancer 2008, 7:5doi:10.1186/1476-4598-7-5

Published:	11 January 2008

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.