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Ursodeoxycholic acid (UDCA) has been regarded as a suppressor of gastrointestinalcancer, but the mechanisms underlying its antitumor effects are not fully understood.Previously, we reported the antitumor effect of UDCA by demonstrating that UDCAinduces apoptosis of gastric cancer cells. Bile acids are known to activate theERK pathway and ERK is a representative oncogenic kinase in cancer cells. Here,we investigated the role of ERK in UDCA-induced gastric cancer cell apoptosis.We found that UDCA enhanced the phosphorylation of ERK1/2 and MEK1/2. The preventionof MEK by the pharmacologic inhibitors PD98059 and U0126, resulted in decreasedUDCA-induced apoptosis as shown by the reduction of apoptotic body formation,caspase-8 activity, and caspase-3, -6 and PARP cleavage, indicating that ERK exertspro-apoptotic activity upon exposure to UDCA. In addition, U0126 reduced UDCA-triggeredTNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) expression. Ingene silencing studies, we observed that RNA interference of ERK2 decreased apoptosisand reduced DR5 overexpression. Lipid raft disrupting agent, methyl-β-cyclodextrin,blunted the phosphorylation of ERK1/2, indicating that ERK activation is regulatedin a lipid raft-dependent manner. On the other hand, tumor-promoting bile acid,deoxycholic acid (DCA), also phosphorylated ERK in SNU601 cells. However, theDCA-triggered ERK pathway exerted anti-apoptotic function in the cells. Suppressionof the ERK pathway enhanced DCA-induced apoptosis, and ERK activation was observedto be lipid raft-independently controlled. These results indicated that UDCA andDCA may cause differential responses in gastric cancer cells through the ERK signalingmolecule. Thus, ERK activation may be a possible mechanism by which UDCA and DCArepresent differential activities in gastrointestinal cancer.

Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells