GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress

Abstract

BACKGROUND Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1-transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis.

Epigenetics Reactivation of Nrf2 in Prostate TRAMP C1 Cells by Curcumin Analogue FN1

“…8, 44–46 Hence, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which induce DNA methylation and histone acetylation modification and gene expression silencing are becoming new targets for prostate cancer prevention and therapy. 17, 47–49 We previously reported that Nrf2 is epigenetically silenced by hypermethylation of the first five CpG islands during prostate cancer development in TRAMP mice and TRAMP-C1 cells.…”

“…Epidemiological, experimental and clinical studies have suggested an association between oxidative stress and risk of PCa development and progression. 8–11 Excessive ROS induce DNA damage and mutation and cell and tissue damage, which could give rise to a variety of human pathogenesis, including cardiovascular, metabolic, inflammatory, and neurodegenerative diseases and cancer. 12–14 …”

Telomeres and telomerase in prostate cancer development and therapy

“…Presumably, the telomerase activity in the postulated epithelial progenitor cells and stem-like cells in BPH would not safeguard against genomic insults from ROS. However, glutathione S -transferase P (GST-P), which is expressed in normal prostate and BPH but not in HGPIN or prostate cancer 107,108 , does have activity against reactive oxidants and electrophiles that could damage DNA 109,110 . Perhaps, BPH is not susceptible to telomere shortening from hyper-proliferation and oxidative DNA damage because of the maintenance activity of telomerase in postulated epithelial progenitor cells and stem-like cells 57 and the detoxification activity of GST-P 50 , respectively.…”

Evaluation of glutathione S‐transferase pi 1 expression and gene promoter methylation in Moroccan patients with urothelial bladder cancer

“…It has been shown that promoter hypermethylation is an epigenetic mechanism able to repress gene transcription by inhibiting the binding of transcription factors to their consensus sequences when methylated (Herman & Baylin, ). In the studies cited above, downregulation of GSTP1 gene expression was associated to an aberrant methylation in the promoter region (Chan et al., ; Li et al., ; Lin et al., ; Martignano et al., ; Mian et al., ; Shilpa et al., ; Zelic et al., ; Zhang et al., ). Moreover, promoter methylation of GSTP1 gene was detected in some body fluids of patients with prostate cancer and was proposed as a biomarker candidate for noninvasive detection of prostate cancer (Cairns et al., ; Goessl et al., ).…”