Document Detail


Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1.
MedLine Citation:
PMID:  22833520     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 H2 O2 -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 H2 O2 , 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 reexpression of GSTP1, which protected the cells from H2 O2 -mediated DNA damage through decreased ROS production compared to nonexposed 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.
Authors:
Rajnee Kanwal; Mitali Pandey; Natarajan Bhaskaran; Gregory T Maclennan; Pingfu Fu; Lee E Ponsky; Sanjay Gupta
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-25
Journal Detail:
Title:  Molecular carcinogenesis     Volume:  53     ISSN:  1098-2744     ISO Abbreviation:  Mol. Carcinog.     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2013-12-17     Completed Date:  2014-02-21     Revised Date:  2014-05-14    
Medline Journal Info:
Nlm Unique ID:  8811105     Medline TA:  Mol Carcinog     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8-18     Citation Subset:  IM    
Copyright Information:
© 2013 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Catechin / analogs & derivatives,  pharmacology
Cell Line
DNA Damage*
Deoxyguanosine / analogs & derivatives,  metabolism
Enzyme Activation
Epithelial Cells / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Glutathione S-Transferase pi / genetics,  metabolism*
Guanosine Triphosphate / pharmacology
Humans
Hydrogen Peroxide / pharmacology
Male
Oxidative Stress* / drug effects,  genetics
Prostate / metabolism*
Prostatic Neoplasms / genetics,  metabolism
Reactive Oxygen Species / metabolism
Grant Support
ID/Acronym/Agency:
R01 AT002709/AT/NCCAM NIH HHS; R01 AT002709/AT/NCCAM NIH HHS; R01 CA108512/CA/NCI NIH HHS; R01 CA108512/CA/NCI NIH HHS; R01 CA115491/CA/NCI NIH HHS; R01 CA115491/CA/NCI NIH HHS; R21 CA109424/CA/NCI NIH HHS; R21 CA109424/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Reactive Oxygen Species; 86-01-1/Guanosine Triphosphate; 88847-89-6/8-oxo-7-hydrodeoxyguanosine; 8R1V1STN48/Catechin; BBX060AN9V/Hydrogen Peroxide; BQM438CTEL/epigallocatechin gallate; EC 2.5.1.18/Glutathione S-Transferase pi; G9481N71RO/Deoxyguanosine
Comments/Corrections

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