ERβ and NFκB—Modulators of Zearalenone-Induced Oxidative Stress in Human Prostate Cancer Cells

Abstract

Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) is commonly expressed in prostate cancer (PCa) cells and is associated with increased proliferation, metastases and androgen independence. Zearalenone (ZEA) is one of the most common mycotoxins contaminating food, which might mimic estrogens and bind to estrogen receptors (ERs). The ratio of androgens to estrogens in men decreases physiologically with age, and is believed to participate in prostate carcinogenesis. In this study, we evaluated the role of NFκB and ERβ in the induction of oxidative stress in human PCa cells by ZEA. As observed, ZEA at a dose of 30 µM induces oxidative stress in PCa cells associated with DNA damage and G2/M cell cycle arrest. We also observed that the inhibition of ERβ and NFΚB via specific inhibitors (PHTPP and BAY 117082) significantly increased ZEA-induced oxidative stress, although the mechanism seems to be different for androgen-dependent and androgen-independent cells. Based on our findings, it is possible that the activation of ERβ and NFΚB in PCa might protect cancer cells from ZEA-induced oxidative stress. We therefore shed new light on the mechanism of ZEA toxicity in human cells.

Zearalenone and the Immune Response

“…In human, study of Marton et al [ 103 ], on ovarian epithelial cells investigating the effect of several compounds, ZEA among them on miRNA expression in correlation with cells estrogenic sensitivity observed that ZEA (1, 10, 100, 1000 nM) increased the rate of cell proliferation in direct proportion to ZEA concentration and depending on the presence of ER-α. By contrast, 30 µM of ZEA in prostate cancer cells induced G2/M cell cycle arrest and decreased cell viability compared to control [ 104 ].…”

“…Oxidative stress and inflammation are tightly correlated, reactive oxygen species playing an important role in the progression of inflammatory disorders [ 146 ] which are mainly regulated by the nuclear transcription factor-κB (NF-κB) pathway, the NF-κB receptor playing an essential role as a mediator in the regulation of the innate and adaptive immune responses [ 110 ]. An increase of Nrf2 after ZEA exposure was correlated with a decrease of NF-κB and the experimentally induction of NF-κB [ 22 , 141 ] significantly increased ZEA-induced oxidative stress [ 104 ]. However, the mechanisms by which zearalenone can influence the expression of the genes involved in the inflammatory response is unclear, zearalenone acting both as pro- or anti-inflammatory molecule/agent.…”

Endocrine-Disrupting Chemicals’ (EDCs) Effects on Tumour Microenvironment and Cancer Progression: Emerging Contribution of RACK1

“…This observation is supported by further in vitro studies that reported ZEA, αand β-ZOL to display growth-promoting effects in breast tissue by increasing protein synthesis and lipid metabolism, thus inducing a potential oestrogen positive BC progression [121]. Notably, ZEA has been shown to induce ERα-mediated migration and invasion of PC cells [122], while ERβ and NF-κB were shown to exert a protective role in PC cells against ZEA-induced oxidative stress [123].…”

Ex Vivo and In Vitro Studies Revealed Underlying Mechanisms of Immature Intestinal Inflammatory Responses Caused by Aflatoxin M1 Together with Ochratoxin A

“…Hence, the above explanations might be one-sided to uncover the mechanisms of phlogistic processes caused by toxins. Zearalenone (ZEN), another toxin from Fusarium graminearum , was verified to pose reproductive adverse effects and inflammatory consequences after binding to estrogen receptors, ERα and ERβ, and be responsible for the stimulation of gene of NF-κB [ 80 ]. Liu et al (2019) proved aryl hydrocarbon receptor (AhR) played a key role in the transcriptional activation of CYP1A5 by T-2 toxin, thereafter reducing cell viability, causing oxidative stress and inducing DNA damage as well as apoptosis [ 81 ].…”