Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1.
Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1.
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DOI：
10.1002/mc.21939
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发表时间：
2014-01
影响因子：
4.6
通讯作者：
Gupta, Sanjay
中科院分区：
文献类型：
--
作者：
Kanwal, Rajnee;Pandey, Mitali;Bhaskaran, Natarajan;MacLennan, Gregory T.;Fu, Pingfu;Ponsky, Lee E.;Gupta, Sanjay
Pi类谷胱甘肽S-转移酶（GSTP 1）积极保护细胞免受致癌物质和亲电子化合物的侵害。通过启动子高甲基化导致的GSTP 1表达缺失是在人前列腺癌中观察到的最常见的表观遗传学改变。GSTP 1的沉默可增加细胞中活性氧（ROS）的产生和DNA损伤。在这项研究中，我们调查了GSTP 1的丢失是否会增加DNA损伤，从而使男性患前列腺癌的风险更高。我们发现，与良性肿瘤相比，腺癌中8-氧代-2 ′-脱氧鸟苷（8-OHdG）水平显著升高（103%; P<0.0001），8-OHdG是一种氧化性DNA损伤标志物，与GST 1活性丧失（34%; P<0.0001）呈正相关（r=0.2）。在正常人前列腺上皮细胞RWPE 1中使用siRNA方法沉默GSTP 1导致细胞内ROS产生增加和细胞对H2 O2介导的氧化应激的更高易感性。此外，人前列腺癌LNCaP细胞，其中包含一个沉默的GSTP 1基因，基因修饰，组成型表达高水平的GSTP 1。GSTP 1活性的诱导降低了LNCaP-pLPCX-GSTP 1细胞中的内源性ROS水平，并且当暴露于H2 O2时，与载体对照LNCaP-pLPCX细胞相比，这些细胞表现出显著降低的ROS产生和8-OHdG水平。此外，LNCaP细胞暴露于绿色茶多酚引起GSTP 1的重新表达，与未暴露的细胞相比，GSTP 1通过减少ROS产生来保护细胞免受H2 O2介导的DNA损伤。这些结果表明，在人类前列腺细胞中GSTP 1表达的损失，增加其对氧化应激诱导的DNA损伤的易感性的过程，可能是前列腺癌的一级预防的重要目标。
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.
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影响因子：
3.8
作者：
Chow, H.-H. Sherry;Hakim, Iman A.;Alberts, David S.
通讯作者：
Alberts, David S.
影响因子：
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4.2
作者：
Lii, Chong-Kuei;Liu, Kai-Li;Tsai, Chia-Wen
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Tsai, Chia-Wen