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

Authors

  • Rajnee Kanwal,

    1. Department of Urology, Case Western Reserve University, Cleveland, Ohio
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  • Mitali Pandey,

    1. Department of Urology, Case Western Reserve University, Cleveland, Ohio
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  • Natarajan Bhaskaran,

    1. Department of Urology, Case Western Reserve University, Cleveland, Ohio
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  • Gregory T. MacLennan,

    1. Department of Pathology, Case Western Reserve University, Cleveland, Ohio
    2. Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio
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  • Pingfu Fu,

    1. Department of Pathology, Case Western Reserve University, Cleveland, Ohio
    2. Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio
    3. Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio
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  • Lee E. Ponsky,

    1. Department of Urology, Case Western Reserve University, Cleveland, Ohio
    2. Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio
    3. The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio
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  • Sanjay Gupta

    Corresponding author
    1. Department of Urology, Case Western Reserve University, Cleveland, Ohio
    2. Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio
    3. The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio
    4. Department of Nutrition, Case Western Reserve University, Cleveland, Ohio
    • Department of Urology, Case Western Reserve University, University Hospitals Case Medial Center, 2109 Adelbert Road, Wood Research Tower, Cleveland, OH 44106.

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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 reexpression of GSTP1, which protected the cells from H2O2-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. © 2013 Wiley Periodicals, Inc.

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