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

Abstract
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.
AuthorsSung-Chul Lim, Hong-Quan Duong, Keshab Raj Parajuli, Song Iy Han
JournalOncology reports (Oncol Rep) Vol. 28 Issue 4 Pg. 1429-34 (Oct 2012) ISSN: 1791-2431 [Electronic] Greece
PMID22824956 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Butadienes
  • Flavonoids
  • Nitriles
  • Protein Kinase Inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • U 0126
  • Ursodeoxycholic Acid
  • MAP2K2 protein, human
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Caspases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Topics
  • Apoptosis (drug effects)
  • Butadienes (pharmacology)
  • Caspases (metabolism)
  • Cell Line, Tumor
  • Enzyme Activation (drug effects)
  • Flavonoids (pharmacology)
  • Humans
  • MAP Kinase Kinase 1 (metabolism)
  • MAP Kinase Kinase 2 (metabolism)
  • MAP Kinase Signaling System (drug effects)
  • Membrane Microdomains (drug effects, metabolism)
  • Nitriles (pharmacology)
  • Phosphorylation (drug effects)
  • Protein Kinase Inhibitors (pharmacology)
  • Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
  • Stomach Neoplasms (drug therapy, metabolism, pathology)
  • Ursodeoxycholic Acid (pharmacology)

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