Pharmacological inhibition of platelet-tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells

Alessandro Sgambato, Melania Dovizio, Thorsten J. Maier, Sara Alberti, Luigia Di Francesco, Emanuela Marcantoni, Gotz Munch, Constance M. John, Beatrix Suess, Dieter Steinhilber, Paola Patrignani

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70 Citazioni (Scopus)


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.
Lingua originaleEnglish
pagine (da-a)25-40
Numero di pagine16
RivistaMolecular Pharmacology
Stato di pubblicazionePubblicato - 2013


  • Binding Sites
  • Blood Platelets
  • Cell Communication
  • Cell Line, Tumor
  • Colonic Neoplasms
  • Cyclin B1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Dinoprostone
  • Down-Regulation
  • Epithelial-Mesenchymal Transition
  • Galectin 3
  • Gene Expression
  • Glycoproteins
  • HT29 Cells
  • Humans
  • Immunoglobulin Fc Fragments
  • Lactones
  • Lactose
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • Receptors, Collagen
  • Sulfones
  • Up-Regulation


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