ERK/MAPK activation involves hypoxia-induced MGr1-Ag/37LRP expression and contributes to apoptosis resistance in gastric cancer

✍ Scribed by Lili Liu; Hongbo Zhang; Li Sun; Yuqi Gao; Haifeng Jin; Shuhui Liang; Yanxia Wang; Mingqing Dong; Yongquan Shi; Zhichao Li; Daiming Fan

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: French
• Weight: 860 KB
• Volume: 127
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.25098

✦ Synopsis

Abstract

We previously demonstrated that hypoxia increased the hypoxia‐inducible factor (HIF‐1)–dependent MGr1‐Ag/37LRP expression, which enhanced adhesion of gastric cancer cells to laminin, inhibited drug‐induced apoptosis and caused cell adhesion–mediated drug resistance (CAM‐DR). Here, we investigated the role of extracellular‐regulated kinase (ERK) 1/2 in the signaling mechanisms underlying these events. We found that hypoxia activated ERK activity in vitro and in vivo. Overexpression of mitogen‐activated protein kinase (MAPK) kinase (MEK), which preferentially activated ERK, mimics, in a nonadditive way, hypoxia‐induced activity of MGr1‐Ag/37LRP promoter and expression of MGr1‐Ag/37LRP. Furthermore, U0126, the MEK inhibitor, inhibited hypoxia‐ and MEK‐induced MGr1‐Ag/37LRP promoter activity in a dose‐dependent manner. MEK inhibition also reversed hypoxia‐ and MEK‐induced HIF‐1 protein and its activity in a dose‐dependent manner. We also investigated reactive oxygen species signaling this response. Exogenous addition of H~2~O~2~ was sufficient to activate ERK in a dose‐dependent profile. Reactive oxygen species scavengers of H~2~O~2~ significantly inhibited hypoxia‐induced ERK or HIF‐1 activation and sequential expression of MGr1‐Ag/37LRP. We also investigated the signaling in hypoxia‐induced cell adhesion and apoptosis induced by vincristine. Hypoxia significantly enhanced adhesion of SGC7901 cells to laminin in a time‐dependent manner, which might be inhibited by the MEK inhibitor U0126 and MGr1‐Ag/37LRP siRNA. Consistent with results of adhesion assay, hypoxia‐resistant apoptosis might be reversed by U0126 in a dose‐dependent manner. Our results suggest that hypoxia‐elicited MGr1‐Ag/37LRP expression activated by HIF‐1 depends on ERK activation. These events are dependent of reactive oxygen intermediates.