Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells.
Fas ligand (FasL/CD95L) is a member of the tumour necrosis factor superfamily that triggers apoptosis following crosslinking of the Fas receptor. Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level. Conversely, stimulation with PGE(2) increased FasL expression and these cells showed increased cytotoxicity against Fas-sensitive Jurkat T cells. Prostaglandin E(2)-induced FasL expression was mediated by signalling via the EP1 receptor. Moreover, immunohistochemical analysis using serial sections of human colon adenocarcinomas revealed a strong positive correlation between COX-2 and FasL (r=0.722; P<0.0001) expression, and between EP1 receptor and FasL (r=0.740; P<0.0001) expression, in the tumour cells. Thus, these findings indicate that PGE(2) positively regulates FasL expression in colon tumour cells, adding another pro-neoplastic activity to PGE(2).
O'Callaghan
G
G
Department of Medicine, University College Cork, National University of Ireland, Clinical Science Building, Cork University Hospital, Wilton, Cork, Ireland.
Kelly
J
J
Shanahan
F
F
Houston
A
A
D015153:Blotting, Western; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015232:Dinoprostone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015398:Signal Transduction
D053222:Fas Ligand Protein; C545635:PTGER1 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015232:Dinoprostone