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


CONCLUSIONS
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.
Cheng
Fan
F
Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA. fxc155@psu.edu
McLaughlin
Patricia J
PJ
Verderame
Michael F
MF
Zagon
Ian S
IS
D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D018450:Disease Progression; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering; D011957:Receptors, Opioid / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D011957:Receptors, Opioid; D016160:Retinoblastoma Protein; C033593:methionine-enkephalin receptor; D004744:Enkephalin, Methionine; C027511:enkephalin-Met, Arg(6)-Phe(7)-; D051357:Cyclin-Dependent Kinase 2