1307 RELATIONSHIP BETWEEN GLUTATHIONE-S-TRANSFERASE PI EXPRESSION AND OXIDATIVE DNA DAMAGE IN HUMAN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 20121307 RELATIONSHIP BETWEEN GLUTATHIONE-S-TRANSFERASE PI EXPRESSION AND OXIDATIVE DNA DAMAGE IN HUMAN PROSTATE CANCER Rajnee Kanwal, Pingfu Fu, Lee Ponsky, and Sanjay Gupta Rajnee KanwalRajnee Kanwal Cleveland, OH More articles by this author , Pingfu FuPingfu Fu Cleveland, OH More articles by this author , Lee PonskyLee Ponsky Cleveland, OH More articles by this author , and Sanjay GuptaSanjay Gupta Cleveland, OH More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1654AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The pi-class glutathione S-transferase (GSTP1) has been described as a ‘caretaker' gene, as it actively protects the cell from oxidative genome damage mediated by carcinogens and electrophilic compounds. Loss of GSTP1 expression via promoter hypermethylation is one of the most common epigenetic alterations observed in human prostate cancer. Silencing of GSTP1 can increase prostate epithelial cells more vulnerable to both oxidant and electrophile carcinogens and causes genetic aberrations leading to increased risk of tumor progression. Observations suggest that increased reactive oxygen species (ROS) causes DNA damage in cells, as measured by 8-hydroxy-2'-deoxyguanosine (8-OHdG), contribute to increased incidence of prostate cancer. However there are no studies which demonstrate correlation between GSTP1 protein/activity and DNA damage in prostate cancer. METHODS We used a panel of 24 human prostate specimens, pair-matched primary tumor and adjacent nontumorous (benign) tissue. Oxidative DNA damage, GSTP1 protein expression/activity, and GSTP1 promoter methylation was assessed. GSTP1 over-expression technique was used to assess H2O2-mediated DNA damage in prostate cancer cells. RESULTS The 8-OHdG levels in DNA of prostate cancer tissues ranged from 0.307 to 0.609ng/μg DNA, whereas the levels in benign tissue range from 0.156 to 0.322ng/μg DNA, respectively. 8-OHdG and GSTP1 promoter methylation levels were higher in adenocarcinoma compared to their benign counterparts, which positively correlated (P=0.533) with the loss of GSTP1 activity. The GSTP1 protein activity of prostate cancer tissues ranged from 738.2 to 1754.4ng/mg protein, whereas the levels in benign tissue range from 1728.6 to 2580.4ng/mg protein. The loss of GSTP1 expression in cells might increase their vulnerability to cytotoxicity and reactive oxygen species (ROS)-mediated DNA damage. In further experiments, human prostate carcinoma LNCaP cells, which contains a silenced GSTP1 gene, was genetically modified to constitutively express high levels of GSTP1. Introduction of GSTP1 lowered endogenous ROS levels in LNCaP cells; treatment with H2O2 significantly reduced ROS and 8-OHdG in LNCaP-GSTP1 cells, compared to parental cell line. Furthermore, treatment with green tea polyphenols to LNCaP cells caused re-expression of GSTP1 which protected the cells from H2O2-mediated DNA damage compared to pretreated cells. CONCLUSIONS These results suggest that oxidative stress-induced DNA damage may be an important measure for primary prevention of prostate cancer. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e530 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rajnee Kanwal Cleveland, OH More articles by this author Pingfu Fu Cleveland, OH More articles by this author Lee Ponsky Cleveland, OH More articles by this author Sanjay Gupta Cleveland, OH More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...