title: Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1.
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.
authors.affiliation: Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany.
authors.forename: Melina
authors.initials: M
authors.lastname: Schellhorn
authors.affiliation: Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Haustein
authors.affiliation: Electron Microscopy Center, Rostock University Medical Center, Rostock, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Frank
authors.affiliation: Section of Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
authors.affiliation: Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hinz
mesh_terms: D000068579:Celecoxib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C573420:ICAM1 protein, human; D018799:Intercellular Adhesion Molecule-1; D000068579:Celecoxib
keywords: celecoxib; immune surveillance; intercellular adhesion molecule 1; lung cancer cells; lymphokine-activated killer cells