Seo Jaesung, Lee Seung-H, Park Soo-Y, Jeong Mi-H, Lee Soo Y, Kim Mi-J, Yoo Jung-Y, Jang Subhin, Choi Kyung-C, Yoon Ho-G
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Korea.
J Cell Biochem. 2019 Feb;120(2):2532-2539. doi: 10.1002/jcb.27545. Epub 2018 Sep 11.
Gastric cancer is the fourth most common cancer worldwide. Despite the high incidence of gastric cancer, efficient chemotherapy treatments still need to be developed. In this study, we examined the anticancer effects of endoplasmic reticulum (ER) stress inducer tunicamycin in gastric cancer. Previously, we found that overexpression of WLS1/GPR177 correlated with poor prognosis in patients with gastric cancer. Furthermore, tunicamycin treatment downregulated GPR177 expression in a dose-dependent manner. GPR177 transports WNT ligand from ER to the plasma membrane, mediating its secretion to the extracellular matrix. In gastric cancer cells, GPR177 preferentially localizes to the ER. Small interfering RNA-mediated knockdown of GPR177 leads to sensitization to ER stress and induces apoptosis of cancer cells along with tunicamycin treatment. GPR177 suppression promoted the ER stress-mediated proapoptotic pathway, such as PERK-CHOP cascade. Furthermore, fluorouracil treatment combined with tunicamycin dramatically reduced cancer cell proliferation. Efficacy of tunicamycin chemotherapy treatments depended on GPR177 expression in gastric cancer cell lines. Together, our results indicate that ER stress can potentiate anticancer effects and suggest GPR177 as a potential gastric cancer therapeutic target.
