Suppression of urokinase plasminogen activator receptor inhibits proliferation and migration of pancreatic adenocarcinoma cells via regulation of ERK/p38 signaling.
Pancreatic ductal adenocarcinoma (PDAC) expresses high levels of urokinase-type plasminogen activator (uPA), its receptor (uPAR) and plasminogen activator inhibitor (PAI)-2, which may play an important role in PDAC progression. The overexpression of uPAR predicted short survival in PDAC patients. In this study, two different PDAC cell lines were used to examine the effect of small interfering (si) RNAs to uPAR, uPA and PAI-2 on proliferation, apoptosis, migration and MAP kinase activation. In both PDAC cell lines, siRNA to uPAR significantly inhibited cell proliferation and migration and stimulated apoptosis, to a greater extent than uPA siRNA. When either PDAC cell line was treated with uPAR siRNA, the level of phosphorylated ERK (p-ERK) decreased substantially, whereas phosphorylated p38 (p-p38) increased when compared to non-silencing control, uPA siRNA or PAI-2 siRNA treatment. This resulted in enhancement of the p-p38/p-ERK ratio which favors cancer cell arrest. Interestingly, uPAR protein expression was suppressed by p-ERK inhibition and stimulated with p-p38 inhibition, suggesting the presence of a positive feedback loop between uPAR and ERK. In summary, our data indicate that, of the uPA system, uPAR exerts the strongest effects on PDAC cells, by acting through the ERK signaling pathway via a positive feedback loop. Disruption of this loop with uPAR siRNA or inhibitor of p-ERK, inhibits PDAC proliferation and migration and promotes apoptosis. These findings suggest that uPAR strongly contributes to PDAC progression and may be considered as a potential anti-pancreatic cancer target.
Department of Surgery, The University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
Aiqun
A
Xue
Meilang
M
Xue
Christopher
C
Jackson
Ross C
RC
Smith
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D017396:Plasminogen Activator Inhibitor 2; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D053148:Caspase 3