Secretory Phospholipase A2 Inhibition Attenuates Intercellular Adhesion Molecule-1 Expression in Human Esophageal Adenocarcinoma Cells

Background. Esophageal adenocarcinoma is an aggressive malignancy, with most patients succumbing to metastatic disease. The presence of intercellular adhesion molecule-1 (ICAM-1) in these cancer cells contributes to their metastatic potential. The ICAM-1 production in other cell types is stimulated by the actions of phospholipase enzymes. We hypothesize that inhibition of the enzyme secretory phospholipase A(2) (sPLA(2)), which contributes to the growth potential of normal esophageal mucosa and esophageal cancer cells, may attenuate ICAM-1 production and nuclear factor-kappa beta activation in human esophageal adenocarcinoma cells. Methods. The FLO-1 verified human esophageal adenocarcinoma cells were treated with 5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino) pentanoic acid, a specific inhibitor of group IIa sPLA(2) (5 mu M, 10 mu M, and 15 mu M doses), followed by tumor necrosis factor-alpha stimulation (20 ng/mL). Cells and medium were collected and analyzed by immunoblotting, flow cytometry, and enzyme-linked immunosorbent assay. Statistical analysis was performed using analysis of variance with the Fisher's least significant difference post-hoc test. Results. Treatment with sPLA(2) inhibitor attenuated total cellular ICAM-1 expression in a dose-dependent manner (p < 0.005). Cell-surface and secreted ICAM-1 expression decreased significantly with sPLA(2) inhibitor treatment (p < 0.001 and p < 0.05, respectively). sPLA(2) inhibition attenuated nuclear factor-kappa beta activation dose-dependently (p < 0.05). Conclusions. Esophageal adenocarcinoma has significant metastatic potential, and inhibiting its metastasis would significantly advance the treatment of this disease. We demonstrate here that treatment of human esophageal adenocarcinoma cells with sPLA(2) inhibitor attenuates the expression of ICAM-1, a marker of metastatic potential, and nuclear factor-kappa beta activation, suggesting a common pathway between the two. These findings identify inhibition of sPLA(2) as a potential therapeutic target for esophageal adenocarcinoma.