Ursodeoxycholic acid (UDCA) has been regarded as a suppressor of
gastrointestinal cancer, but the mechanisms underlying its antitumor effects are not fully understood. Previously, we reported the antitumor effect of UDCA by demonstrating that UDCA induces apoptosis of
gastric cancer cells.
Bile acids are known to activate the ERK 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 prevention of
MEK by the pharmacologic inhibitors
PD98059 and
U0126, resulted in decreased UDCA-induced apoptosis as shown by the reduction of apoptotic body formation,
caspase-8 activity, and
caspase-3, -6 and PARP cleavage, indicating that ERK exerts pro-apoptotic activity upon exposure to UDCA. In addition,
U0126 reduced UDCA-triggered
TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) expression. In gene silencing studies, we observed that RNA interference of ERK2 decreased apoptosis and reduced DR5 overexpression.
Lipid raft disrupting agent, methyl-β-
cyclodextrin, blunted the phosphorylation of ERK1/2, indicating that ERK activation is regulated in a
lipid raft-dependent manner. On the other hand,
tumor-promoting
bile acid,
deoxycholic acid (DCA), also phosphorylated ERK in SNU601 cells. However, the DCA-triggered ERK pathway exerted anti-apoptotic function in the cells. Suppression of the ERK pathway enhanced DCA-induced apoptosis, and ERK activation was observed to be
lipid raft-independently controlled. These results indicated that UDCA and DCA may cause differential responses in
gastric cancer cells through the ERK signaling molecule. Thus, ERK activation may be a possible mechanism by which UDCA and DCA represent differential activities in
gastrointestinal cancer.