Proteinase-activated receptor 2 (PAR(2)) in cholangiocarcinoma (CCA) cells: effects on signaling and cellular level.
In this study, we demonstrate functional expression of the proteinase-activated receptor 2 (PAR(2)), a member of a G-protein receptor subfamily in primary cholangiocarcinoma (PCCA) cell cultures. Treatment of PCCA cells with the serine proteinase trypsin and the PAR(2)-selective activating peptide, furoyl-LIGRLO-NH(2), increased migration across a collagen membrane barrier. This effect was inhibited by a PAR(2)-selective pepducin antagonist peptide (P2pal-18S) and it was also blocked with the Met receptor tyrosine kinase (Met) inhibitors SU 11274 and PHA 665752, the MAPKinase inhibitors PD 98059 and SL 327, and the Stat3 inhibitor Stattic. The involvement of Met, p42/p44 MAPKinases and Stat3 in PAR(2)-mediated PCCA cell signaling was further supported by the findings that trypsin and the PAR(2)-selective agonist peptide, 2-furoyl-LIGRLO-NH(2), stimulated activating phosphorylation of these signaling molecules in cholangiocarcinoma cells. With our results, we provide a novel signal transduction module in cholangiocarcinoma cell migration involving PAR(2)-driven activation of Met, p42/p44 MAPKinases and Stat3.
Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Medical Faculty at the Friedrich Schiller University Jena, University Hospital Jena, Drackendorfer Str. 1, 07747 Jena, Germany. roland.kaufmann@med.uni-jena.de
Roland
R
Kaufmann
Alexander
A
Hascher
Franziska
F
Mussbach
Petra
P
Henklein
Kathrin
K
Katenkamp
Martin
M
Westermann
Utz
U
Settmacher
D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology*; D003499:Cyclic S-Oxides / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D003499:Cyclic S-Oxides; D005419:Flavonoids; D007211:Indoles; D010455:Peptides; D010879:Piperazines; D044464:Receptor, PAR-2; C424127:SL 327; D013449:Sulfonamides; D013450:Sulfones; C517409:stattic; D000607:Aminoacetonitrile; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one