Protection against oxidative DNA damage and stress in human prostate by glutathione S‐transferase P1

Abstract

The pi-class glutathione S-transferase (GSTP1) actively protect cells from carcinogens and electrophilic compounds. Loss of GSTP1 expression via promoter hypermethylation is the most common epigenetic alteration observed in human prostate cancer. Silencing of GSTP1 can increase generation of reactive oxygen species (ROS) and DNA damage in cells. In this study we investigated whether loss of GSTP1 contributes to increased DNA damage that may predispose men to a higher risk of prostate cancer. We found significantly elevated (103%; P<0.0001) levels of 8-oxo-2′-deoxogunosine (8-OHdG), an oxidative DNA damage marker, in adenocarcinomas, compared to benign counterparts, which positively correlated (r=0.2) with loss of GSTP1 activity (34%; P<0.0001). Silencing of GSTP1 using siRNA approach in normal human prostate epithelial RWPE1 cells caused increased intracellular production of ROS and higher susceptibility of cells to H2O2-mediated oxidative stress. Additionally, human prostate carcinoma LNCaP cells, which contain a silenced GSTP1 gene, were genetically modified to constitutively express high levels of GSTP1. Induction of GSTP1 activity lowered endogenous ROS levels in LNCaP-pLPCX-GSTP1 cells, and when exposed to H2O2, these cells exhibited significantly reduced production of ROS and 8-OHdG levels, compared to vector control LNCaP-pLPCX cells. Furthermore, exposure of LNCaP cells to green tea polyphenols caused re-expression of GSTP1, which protected the cells from H2O2-mediated DNA damage through decreased ROS production compared to non-exposed cells. These results suggest that loss of GSTP1 expression in human prostate cells, a process that increases their susceptibility to oxidative stress-induced DNA damage, may be an important target for primary prevention of prostate cancer.

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

“…Molecular modeling and docking studies supported the binding of EGCG to DNMT3B in HeLa cells [108]. EGCG (5-20 μM) or Pholyphenon E® (1-10 μg/mL) treatments of different PCa cell lines, have determined a dose-and time-dependent reexpression of GSTP1 enzyme concomitantly with the down-regulation of DNMT1 [41,106]. The reexpression of GSTP1, induced by treatment with EGCG or Polyphenon E® may be, at least in part, responsible for the quenching of free radicals species and reduction of DNA damage associated with oxidative stress [41].…”

“…Kanwal and colleagues treated LNCaP cells with EGCG (20 μM) or Polyphenon E® (10 μg/mL), a standardized GTCs-enriched mixture, caffeine free, containing 80% to 98% total catechins by weight. The Authors have demonstrated that the 72 h-treatments make cells more resistant to both H2O2-induced oxidative stress and DNA damage [41].…”

“…EGCG (5-20 μM) or Pholyphenon E® (1-10 μg/mL) treatments of different PCa cell lines, have determined a dose-and time-dependent reexpression of GSTP1 enzyme concomitantly with the down-regulation of DNMT1 [41,106]. The reexpression of GSTP1, induced by treatment with EGCG or Polyphenon E® may be, at least in part, responsible for the quenching of free radicals species and reduction of DNA damage associated with oxidative stress [41]. Two studies concluded that GTCs did not produce a significant effect on DNA methylation in PCa cell lines and in TRAMP mice [109,110].…”

Effect of Chromium on Glutathione-S-Transferase and Catalase Activity and their Respective Gene Expressions in the Brain Tissue of F1 Generation Mice Following Prenatal Exposure: Modulation by Quercetin

“…Reports show that CAT activity decreases in oxidative stress Gene expression for CAT Schizosaccharomyces pompe was enhanced in oxidative stress. Thus the enzyme activity for GST and CAT and their respective gene expression are valuable indicators of oxidative damage occurring in brain [6][7][8][9].…”

Do New Zealand men with prostate cancer benefit from a Mediterranean-style diet?

“…Elevated levels of inflammatory markers have been associated with high-grade prostate cancer in some studies (Shariat et al, 2001;Platz & De Marzo, 2004;Huffman et al, 2006;Gurel et al, 2014) but not in others (Il'yasova et al, 2005;Stark et al, 2009). Systemic inflammation has been associated with earlier cancer mortality (McArdle, Qayyum & McMillan, 2010;Shafique et al, 2012), which adds weight to an argument for a detrimental effect of chronic inflammation and the potential benefit of alow-inflammatory diet.Increased levels of free radicals and pro-oxidant compounds (Arsova-Sarafinovska et al, 2009;Qu et al, 2013;Kanwal et al, 2014), and decreased levels of antioxidant enzymes have been found in prostate tissue (Kanwal et al, 2014), and in association with prostate cancer ( al., 2009). Both prostatic cancer cells and high-grade prostatic intraepithelial neoplasia are notably deficient in the important endogenous antioxidant, glutathione S-transferase (Platz & De Marzo, 2004).…”