Loss of NADPH Quinone Oxidoreductase in the Prostate and Enhanced Serum Levels of Cytokine-Induced Neutrophil Chemoattractant 2α in Hormone-Stimulated Noble Rats: Potential Role in Prostatic Intraepithelial Neoplasia Development

Abstract

The Noble rat is an established model for studying hormone-induced development of prostatic intraepithelial neoplasia and prostatic adenocarcinoma. It is known that for a period, hormones in the prostate generate reactive molecules that have the capacity to overwhelm intracellular defenses, damage macromolecules, and modulate redox-regulated signaling pathways leading to increased oxidative stress. Such hormone-induced imbalance in the oxidative stress/antioxidant defense enzymes may lead to neoplastic transformation of the prostate. We investigated alteration in the expression of critical antioxidant defense enzymes, a redox-regulated transcription factor nuclear factor kappaB (NFkappaB) and its downstream target inflammation-associated cyclooxygenase 2 (Cox-2) in the prostate from hormone-stimulated Noble rats using immunohistochemistry. Further, we also analyzed serum levels of cytokines and chemokines associated with inflammation using multiplex immunoassay. Our results show that there was no significant change in the expression of glutathione peroxidase, glutathione S-transferase pi, superoxide dismutase, or catalase. However, the level of NADPH quinone oxidoreductase decreased in hormone-stimulated animals compared with their unstimulated counterparts. Further, the prostate from hormone-stimulated rats showed very strong expressions of p65, Cox-2, and NFkappaB DNA binding activity. In addition, the cytokine-induced neutrophil chemoattractant 2alpha was significantly upregulated by more than 10-fold (P = .001) in serum from animals stimulated with hormones. Although further studies are required, we speculate that activation of NFkappaB/cytokine-induced neutrophil chemoattractant 2alpha/Cox-2 along with modulation of antioxidant defense mechanisms may create a proinflammatory environment suitable for tumor growth and survival.