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Background/Aims Sulindac metabolites can inhibit the phospho-rylation of extracellular signal-regulated kinase (ERK) 1/2 and induceapoptosis with mechanisms not fully understood. Recently, XIAP-associated factor 1 (XAF1) has been identified to negatively regulatethe function of X-linked inhibitor of apoptosis (XIAP). In this study,we investigated the role of XAF1 in gastric cancer cell lines inducedby ERK1/2 suppression and treatment with sulindac metabolites.Methods Three human gastric cancer cell lines were studied,including AGS (p53 wide type), BCG823 (p53 mutant) and Kato III(p53 deficiency). The effect of U0126 (a MEK-specific inhibitor) onMEK/ERK signaling pathway and XAF1 expression were detected byWestern blotting, so did sulindac metabolites. The growth rate ofBCG823 and its XAF1 stable transfectants were evaluated by MTTassay with or without treatment of two sulindac metabolites, sulfideand sulfone, respectively.Results The original expressions of XAF1 proteins were very lowin AGS and BCG823 cells. But the levels were increased after treat-ment with U0126 (30 uM) for 24 h without down-regulation of XIAP.The expression of XAF1 had no alteration in Kato III cells with orwithout ERK inhibitor. Phospho-p44/42 and p-MEK1/2 proteinlevels were markedly decreased by treatment of U0126 in these threegastric cancer cells. XAF1 expression could also be induced by sulin-dac metabolites, sulfide and sulfone. Both sulfide and sulfone sup-pressed the growth of BCG823 cells. Stable transfection with XAF1rendered BCG823 cells more susceptible to sulindac metabolites-induced apoptosis in doses (Sulfide 60–160 uM, Sulfone 200–600 uM) and time (1–3 days) dependent manner.Conclusions These findings suggested that inactivation of ERK1/2could induce XAF1 expression which may correlate with the differ-ent type of p53 in gastric cancer cells. Over-expression of XAF1 mayimprove the sensitivity of gastric cancer cells to sulindac metabolites.link_to_subscribed_fulltex