Abstract
The oxidative stress response is a cellular defense mechanism that protects cells from oxidative damage and cancer development. The exact molecular mechanism by which reactive oxygen species (ROS) contribute to DNA damage and increase genome instability in prostate cancer merits further investigation. Here, we aimed to determine the effects of NKX3.1 loss on antioxidant defense in response to acute and chronic inflammation in an in vitro model. Oxidative stress-induced DNA damage resulted in increased H2AX(S139) phosphorylation (a hallmark of DNA damage), along with the degradation of the androgen receptor (AR), p53 and NKX3.1, upon treatment with conditioned medium (CM) obtained from activated macrophages or H2O2. Furthermore, the expression and stability of SIRT1 were increased by CM treatment but not by H2O2 treatment, although the level of ATM(S1981) phosphorylation was not changed compared with controls. Moreover, the deregulated antioxidant response resulted in upregulation of the pro-oxidant QSCN6 and the antioxidant GPX2 and downregulation of the antioxidant GPX3 after CM treatment. Consistently, the intracellular ROS level increased after chronic treatment, leading to a dose-dependent increase in the ability of LNCaP cells to tolerate oxidative damage. These data suggest that the inflammatory microenvironment is a major factor contributing to DNA damage and the deregulation of the oxidative stress response, which may be the underlying cause of the increased genetic heterogeneity during prostate tumor progression.
Highlights
Oxidative stress contributes to the initiation, promotion and progression of carcinogenesis
Treatment To determine whether inflammatory cytokine or oxidative exposure is the major factor in reactive oxygen species (ROS)-dependent reduction of androgen receptor (AR), NKX3.1 and p53 protein levels, LNCaP cells were treated with conditioned medium (CM) or H2O2 with or without the antioxidant, N-Acetyl-L-cysteine (LNAC)
The CM treatments resulted in the degradation of AR, p53 and NKX3.1 in a dose-dependent manner, which is consistent with our previous studies [18]
Summary
Oxidative stress contributes to the initiation, promotion and progression of carcinogenesis. ROS are generated in excess amounts during chronic inflammation, and ROSmediated DNA damage alters the genetic composition. This damage may promote oncogenic transformation, which occurs when genes encoding essential factors involved in DNA repair, apoptosis and cell cycle regulation are affected [2]. A number of protein kinase pathways, such as the MAPK pathway, are activated by oxidative signals during inflammation and inflammatory diseases. These pathways synergistically contribute to the activation of cytokine release, and combined with the loss of adhesion and the release of angiogenic factors, they may eventually contribute to cellular proliferation, differentiation
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