title: Pharmacological inhibition of platelet-tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells.
abstract: Cyclooxygenase (COX)-2-derived prostanoids can influence several processes that are linked to carcinogenesis. We aimed to address the hypothesis that platelets contribute to aberrant COX-2 expression in HT29 colon carcinoma cells and to reveal the role of platelet-induced COX-2 on the expression of proteins involved in malignancy and marker genes of epithelial-mesenchymal transition (EMT). Human platelets cocultured with HT29 cells rapidly adhered to cancer cells and induced COX-2 mRNA expression, but not protein synthesis, which required the late release of platelet-derived growth factor and COX-2 mRNA stabilization. Platelet-induced COX-2-dependent prostaglandin E2 (PGE2) synthesis in HT29 cells was involved in the downregulation of p21(WAF1/CIP1) and the upregulation of cyclinB1 since these effects were prevented by rofecoxib (a selective COX-2 inhibitor) and rescued by exogenous PGE2. Galectin-3, which is highly expressed in HT29 cells, is unique among galectins because it contains a collagen-like domain. Thus, we studied the role of galectin-3 and platelet collagen receptors in platelet-induced COX-2 overexpression. Inhibitors of galectin-3 function (β-lactose, a dominant-negative form of galectin-3, Gal-3C, and anti-galectin-3 antibody M3/38) or collagen receptor-mediated platelet adhesion (revacept, a dimeric platelet collagen receptor GPVI-Fc) prevented aberrant COX-2 expression. Inhibition of platelet-cancer cell interaction by revacept was more effective than rofecoxib in preventing platelet-induced mRNA changes of EMT markers, suggesting that direct cell-cell contact and aberrant COX-2 expression synergistically induced gene expression modifications associated with EMT. In conclusion, our findings provide the rationale for testing blockers of collagen binding sites, such as revacept, and galectin-3 inhibitors in the prevention of colon cancer metastasis in animal models, followed by studies in patients.
authors.affiliation: Department of Neuroscience and Imaging and Center of Excellence on Aging (CeSI), G. d'Annunzio University, Via dei Vestini, 31, 66100 Chieti, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Dovizio
authors.forename: Thorsten J
authors.initials: TJ
authors.lastname: Maier
authors.forename: Sara
authors.initials: S
authors.lastname: Alberti
authors.forename: Luigia
authors.initials: L
authors.lastname: Di Francesco
authors.forename: Emanuela
authors.initials: E
authors.lastname: Marcantoni
authors.forename: Götz
authors.initials: G
authors.lastname: Münch
authors.forename: Constance M
authors.initials: CM
authors.lastname: John
authors.forename: Beatrix
authors.initials: B
authors.lastname: Suess
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sgambato
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
mesh_terms: D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000097:blood* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D007785:Lactose / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D038981:Receptors, Collagen / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C534699:CCNB1 protein, human; D056744:Cyclin B1; D052246:Cyclooxygenase 2 Inhibitors; D037502:Galectin 3; D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; D007783:Lactones; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D038981:Receptors, Collagen; C559357:Revacept; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D007785:Lactose; D015232:Dinoprostone