K-RAS transformation in prostate epithelial cell overcomes H₂O₂-induced apoptosis via upregulation of gamma-glutamyltransferase-2

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• 作者：Dong-Oh Moon^a ; Bo Yeon Kim^b ; Jae Hyuk Jang^b ; Mun-Ock Kim^b ; R.G.P.T. Jayasooriya^c ; Chang-Hee Kang^c ; Yung Hyun Choi^d ; Sung-Kwon Moon^e ; Wun-Jae Kim^f ; Jong Seog Ahn^b ; ^{jsahn@kribb.re.kr} ; Gi-Young Kim^c ; ^{immunkim@jejunu.ac.kr}
• 关键词：GGT2 ; gamma-glutamyltransferase 2 ; H2O2 ; hydrogen peroxide ; ROS ; reactive oxygen species ; siRNA ; small interfering RNA
• 刊名：Toxicology in Vitro
• 出版年：2012
• 期刊代码：48_08872333
• 类别：pha
• 出版时间：April, 2012
• 卷：26
• 期：3
• 页码：429-434
• 文件大小：580 K

摘要

The anti-apoptotic oncogene K-RAS is hypothesized to increase the antioxidant status of cells, thereby protecting them from generation of reactive oxygen species (ROS). Therefore, we examined whether K-RAS overcomes hydrogen peroxide (H₂O₂)-mediated apoptosis in the human fetal prostate epithelial cell 267B1. In this study, we found that treatment of 267B1 cells with H₂O₂ resulted in significant reduction of cell growth, which was associated with cytochrome-c release and caspase-3 activation. However, mutated K-RAS transformation (268B1/K-RAS) rendered 267B1 cells reduction of the resistance to H₂O₂-induced apoptosis through suppression of ROS generation. In addition, we analyzed profiling of gene expression in K-RAS transformation and found that gamma-glutamyltransferase 2 (GGT2) most highly expressed. Transient knockdown of K-RAS resulted in a significant downregulation of GGT gene expression. We also revealed that expression of GGT2 gene is closely regulated by the ERK signal pathway in 267B1/K-RAS cells. In addition, the anti-apoptotic effect of mutated K-RAS was attenuated by treatment with GGT2 RNA interference through inhibition of ROS generation, suggesting that mutated K-RAS mediates resistance to H₂O₂-induced apoptosis through GGT2 activation. These results importantly provide mechanistic insights on the anti-apoptotic activity of mutated K-RAS.