Oxidative stress is associated with elevated levels of intra
Oxidative stress is associated with elevated levels of intracellular reactive oxygen species (ROS) generation which then causes DNA damage and the death of cells (Miyata et al., 2017). Generation of ROS affects main signaling pathways in cells associated with tumorigenesis: mitogen activated protein kinases pathways (MAPK), nuclear factor κB (NFκB) associated signaling or one of the best known in prostate cancer phosphatase and tensin homolog (PTEN) signaling (Liou and Storz, 2010). ROS generation is also involved in control of cell motility, mainly by modulation of β-catenin and activity of matrix metalloproteinases (MMPs) (Miyata et al., 2017). Estrogens, which play crucial role in developing and maintaining sexual and reproductive functions in humans, participate in the process of carcinogenesis by involvement in ROS-mediated processes (Lau and To, 2016). The effect of estrogen action is mainly triggered by estrogen receptors (ERs), the two most known ERs: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) whose activation influences the cell signaling pathways associated with proliferation, apoptosis, Idoxuridine control, inflammation and epithelial-mesenchymal transition (EMT) (Kowalska and Piastowska-Ciesielska, 2016). ERs might be involved in the ROS-dependent modulation of antioxidant enzyme status through an increase in mitochondrial ROS production (Miró et al., 2011) or well-known association of ERβ and NFκB- hypoxia inducible factor 1 aplha (HIF-1α) signaling in chronic inflammation in prostate (Mak et al., 2015). ERβ is also involved in ROS-induced changes in motility of prostate cells (Grubisha et al., 2012).
ZEA is reported to induce ROS-associated cell death, both through induction of apoptosis and autophagy (Fan et al., 2017, Zheng et al., 2018a, Zheng et al., 2018b), but there is no evidence whether ERs are involved in this process. Thus, in this study, we evaluate whether ZEA might induce oxidative stress in normal epithelial cells and whether that process is associated with ERβ activation. For this purpose, the selective ERβ inhibitor, PHTPP, is used simultaneously with ZEA treatment.
Materials and methods
Discussion Prostate cancer (PCa) is the second solid-cancer in men worldwide and the commonest in the USA (Siegel et al., 2017). Androgens are the main regulators of prostate cancerogenesis, nevertheless the incidence of prostate cancer is very low below the age of 40, and increasing with overall ratio of estrogens to androgens, which indicates that estrogens might also play a crucial role in prostate cancer (Lau and To, 2016). The fact that men with the lowest incidence of PCa (Chinese/Japanese) moving to the USA present similar to American incidence of PCa confirms that diet and life style might be crucial factors in PCa (Shimizu et al., 1991). Naturally occurring estrogens as well as EDC might also play a role in the process of prostate carcinogenesis due to the modulation of overall steroidogenesis (Kowalska et al., 2016). Taking into consideration the well-known hormonal imbalance-inducing effect of ZEA, it is also very possible that ZEA might have an influence on prostate carcinogenesis, which was suggested by us in previous studies (Kowalska et al., 2017). The present study evaluated the effects of high concentrations of ZEA on the induction of oxidative stress in normal epithelial prostate cells as compared to those established by the European Food Safety Authority (ESFA). Moreover, we investigated whether the observed generation of ROS, decrease in cell proliferation, and oxidative stress defense mechanism are associated with activation of ERβ. We observed that ZEA is able to induce oxidative stress in PNT1A cells associated with DNA damage and blockage of cell cycle progression in the G2/M cell cycle phase. ZEA is also able to modulate the activity and expression of SOD and CAT as well as modulates the expression of NOS2 and NOS3. The possible mechanism through which ZEA might induce oxidative stress in PNT1A cells was also studied. The significant decreases in the HIF-1α, FOXO3 and RelA expression indicate the possible molecular mechanism. The blockage of the activity of ERβ showed that ERβ might play a protective role in ZEA-induced oxidative stress in prostate cells, however, this role is not enough to reduce it.