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 epithelialmesenchymal 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 E 2 (PGE 2 ) 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 PGE 2 . 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 plateletinduced COX-2 overexpression. Inhibitors of galectin-3 function (b-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.

Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study

“…Several studies have suggested mechanisms underlying the antitumor effects of aspirin, such as prevention of COX-2 overexpression in tumor cells due to inflammation in the absence of platelets or to direct platelet-tumor cell interaction [10,19] or prevention of this interaction by inhibiting cyclooxygenase-1 (COX-1) in platelets [12]. Although COX-1 is expressed constitutively in various tissues, COX-2 is produced by stimulation such as inflammation [20].…”

Platelets and cancer: a casual or causal relationship: revisited

“…Recently, Dovizio et al showed that the induction of COX-2 overexpression by platelet-tumor cell cross-talk could be inhibited by disrupting galectin-3 function or collagen receptor-mediated platelet adhesion. Their study suggested that blocking physical interactions by targeting collagen binding sites could be an alternate means of affecting COX-2 [529]. …”

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

“…Another mechanism could involve the cleavage of galectin-3 by SspB (as shown here) and by neutrophil-released metalloproteases and serine proteases (25,27,28), impairing the production of immunomodulatory ROS, as well as galectin-3-dependent opsonophagocytic processes, possibly resulting in impaired infection control and aggravated tissue destruction (14,15,24). Furthermore, protease-cleaved galectin-3 (CRD) may possibly have proinflammatory effects per se, contributing to inflammatory tissue damage, as seen in other disease models (51)(52)(53)(54). These suggested mechanisms can appear to work in opposite directions, but opposing functions are well-known phenomena in the galectin field.…”