Abstract
The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. Finally, celecoxib elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate celecoxib-induced upregulation of ICAM-1 on lung cancer cells to be responsible for intercellular ICAM-1/LFA-1 crosslink that confers increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of celecoxib.
Highlights
Celecoxib is a selective inhibitor of the prostaglandin (PG)-synthesizing enzyme cyclooxygenase-2 (COX-2) [1]
To investigate the impact of celecoxib on intercellular adhesion molecule 1 (ICAM-1) expression and tumor cell lysis two human non-small cell lung cancer (NSCLC) cell lines (A549, H460) as well as metastatic cells derived from a lung cancer patient were used
The present study provides first-time proof for celecoxib to induce upregulation of the adhesion molecule ICAM-1 on the surface of tumor cells, resulting in increased tumor cell lysis by lymphokine-activated killer (LAK) cells
Summary
Celecoxib is a selective inhibitor of the prostaglandin (PG)-synthesizing enzyme cyclooxygenase-2 (COX-2) [1]. In matter of lung cancer reports have suggested celecoxib as treatment and preventive option [3,4,5,6] and to enhance the response to preoperative paclitaxel and carboplatin in early-stage non-small cell lung cancer (NSCLC) [7]. Celecoxib was shown to even enhance COX-2 expression and PG formation by lung cancer cells as key events within its proapoptotic action [14]. Celecoxib was found to produce a downregulation of major histocompatibility complex I molecule expression on metastatic breast cancer cells, thereby leading to improved recognition by natural killer (NK) cells conferring an enhanced tumor cell lysis [15]
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