Fibronectin-induced COX-2 mediates MMP-2 expression and invasiveness of rhabdomyosarcoma.
Although accumulating evidence suggests the importance of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) in the pathogenesis of many cancers, the mechanism by which this enzyme and its metabolite promote cancer progression is unknown. In this study, we investigated the role of COX-2 in fibronectin-induced up-regulation of rhabdomyosarcoma matrix metalloproteinase (MMP)-2 activity and cellular invasiveness. We tested three human rhabdomyosarcoma cell lines: RMS559, RD, and SJRH30. Cell attachment to fibronectin up-regulated both COX-2 expression and PGE(2) production and concomitantly enhanced MMP-2 activity. Exogenous PGE(2) stimulated MMP-2 promoter activity, increased MMP-2 expression, and increased cellular invasiveness. Aspirin and rofecoxib (non-selective and selective COX-2 inhibitor, respectively) each abolished fibronectin-associated induction of MMP-2 and induced dose-dependent reductions in cellular invasiveness. These data implicated a role for inducible COX-2 and PGE(2) in the regulation of rhabdomyosarcoma cellular invasiveness and MMP-2 activity.
Ito
Hiromichi
H
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. hito@partners.org
Duxbury
Mark
M
Benoit
Eric
E
Farivar
Robert S
RS
Gardner-Thorpe
James
J
Zinner
Michael J
MJ
Ashley
Stanley W
SW
Whang
Edward E
EE
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D002452:Cell Count; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction; D005353:Fibronectins / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D007797:Laminin / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000201:enzymology* / Q000473:pathology; D013450:Sulfones; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005353:Fibronectins; D007527:Isoenzymes; D007783:Lactones; D007797:Laminin; D008565:Membrane Proteins; D011994:Recombinant Proteins; D013450:Sulfones; C116926:rofecoxib; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020778:Matrix Metalloproteinase 2; D015232:Dinoprostone; D001241:Aspirin