Oxidative Stress Adaptation in Aggressive Prostate Cancer May Be Counteracted by The Reduction of Glutathione Reductase

Abstract

Oxidative stress has been associated with prostate cancer development and progression due to an increase of reactive oxygen species (ROS). However, the mechanisms whereby ROS and the antioxidant system participate in cancer progression remain unclear.

In order to clarify the influence of oxidative stress in prostate cancer progression, we performed this study in two human prostate cancer cell lines, PC3 and HPV10 (from metastasis and from cancer in situ, respectively) and RWPE1 cells derived from normal prostate epithelium. Cells were treated with hydrogen peroxide (H2O2) and PC3 cells were also treated with diethyl maleate (DEM). The effect on cell growth, viability, mitochondria membrane potential and oxidative stress was analyzed. Oxidative stress was evaluated based on ROS production, oxidative lesion of lipids (MDA) and on determination of antioxidants, including enzyme activity of glutathione peroxidase (Gl-Px), glutathione reductase (Gl-Red) and on the quantification of glutathione (GSH), glutathione-s-transferase (GST) and total antioxidant status (TAS).

PC3 shows higher ROS production but also the highest GSH levels and Gl-Red activity, possibly contributing to oxidative stress resistance. This is also associated with higher mitochondrial membrane potential, TAS and lower lipid peroxidation. On the other hand, we identified Gl-Red activity reduction as a new strategy in overcoming oxidative stress resistance, by inducing H2O2 cytotoxicity. Therefore these results suggest Gl-Red activity reduction as a new potential therapeutic approach, in prostate cancer.