Celecoxib modulates adhesion of HT29 colon cancer cells to vascular endothelial cells by inhibiting ICAM-1 and VCAM-1 expression.

BACKGROUND AND PURPOSE: Cyclooxygenase-2 (COX-2) is highly expressed during inflammation and can promote the progression of colorectal cancer. Interactions between cancer cells and vascular endothelial cells are key events in this process. Recently, the selective COX-2 inhibitor, celecoxib, was shown to inhibit expression of the adhesion molecules, ICAM-1 and VCAM-1, in the human colon cancer cell line HT29 and to inhibit adhesion of HT29 cells to FCS-coated plastic wells. Here, we evaluated the effects of celecoxib on adhesion of HT29 cells to human umbilical vein endothelial cells (HUVEC), mediated by ICAM-1 and VCAM-1, to assess further the potential protective effects of celecoxib on cancer development. EXPERIMENTAL APPROACH: Celecoxib was incubated for 4 h with HT29 cells and HUVEC and adhesion was quantified by a computerized micro-imaging system. Expression analysis of ICAM-1 and VCAM-1 cell adhesion molecules was performed by western blot. KEY RESULTS: Celecoxib (1 nM-10 microM) inhibited, with the same potency, adhesion of HT29 cells to resting HUVEC or to HUVEC stimulated by tumour necrosis factor-alpha (TNF-alpha), mimicking inflammatory conditions. Analysis of ICAM-1 and VCAM-1 expression showed that celecoxib inhibited expression of both molecules in TNF-alpha-stimulated HUVEC, but not in resting HUVEC; inhibition was concentration-dependent and maximal (about 50%) at 10 microM celecoxib. CONCLUSIONS AND IMPLICATIONS: In conclusion, our data show that celecoxib inhibits HT29 cell adhesion to HUVEC and expression of ICAM-1 and VCAM-1, in stimulated endothelial cells. These effects may contribute to the chemopreventive activity of celecoxib in the development of colorectal cancer.

Celecoxib decreases expression of the adhesion molecules ICAM-1 and VCAM-1 in a colon cancer cell line (HT29).

BACKGROUND AND PURPOSE: We investigated the ability of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, to modulate expression of ICAM-1 and VCAM-1 in the colon cancer cell line HT29. EXPERIMENTAL APPROACH: We analysed the effect of celecoxib on ICAM-1 and VCAM-1 protein and mRNA expression in HT29 cells. Experiments were performed in the presence of mitogen-activated protein kinases (MAPK) inhibitors to evaluate the involvement of these kinases in this phenomenon. We evaluated adhesion of HT29 cells to FCS-coated plastic wells in the presence of celecoxib or MAPK inhibitors. Furthermore, we studied the effect of celecoxib on apoptosis. KEY RESULTS: Celecoxib down-regulated ICAM-1 and VCAM-1 expression in HT29 cells in a time- and dose-dependent way. Celecoxib reduced activation of p38 and p55 c-Jun terminal NH(2) kinase (JNK) MAPKs, but did not affect p46 JNK or p42/44 MAPK phosphorylation. Pretreatment with SB202190 or SP600125, specific inhibitors of p38 and JNK MAPKs, respectively, reduced ICAM-1 and VCAM-1 expression in HT29 cells dose-dependently. Adhesion of HT29 cells to FCS-coated plastic wells was inhibited dose-dependently by celecoxib, and also by SB202190 and SP600125. Celecoxib showed a pro-apoptotic effect, inducing Bax and BID but down-regulating Bcl-2. CONCLUSIONS AND IMPLICATIONS: Our findings show that celecoxib caused down-regulation of ICAM-1 and VCAM-1, affecting the adhesive properties of HT29 cells in a COX-2 independent way, inhibiting p38 and p55 MAPKs and activating a pro-apoptotic pathway.