zearalenone and Prostatic-Neoplasms

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.

Topics: Cell Culture Techniques; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Cell Survival; DNA Damage; Estrogen Receptor beta; Humans; Male; NF-kappa B; Oxidative Stress; PC-3 Cells; Prostatic Neoplasms; Protein Binding; Reactive Oxygen Species; Zearalenone

Zearalenone (ZEA) is a nonsteroidal mycotoxin produced by several fungi of the genus Fusarium spp. It is known to play various roles in the regulation of the prostate cancer cell cycle, including carcinogenesis. The present study evaluates the influence of ZEA on the mitochondrial metabolism, plasma membrane permeabilization and cell cycle of prostate cancer cells. At concentrations of 100 nM and 0.3 nM, ZEA caused a decrease in the oxidative activity of mitochondria, as well as increases in LDH release, apoptosis induction and the number of cells in the G0/G1 phase. The opposite effect was observed for lower concentrations (0.1 nM and 0.001 nM). These in vitro studies indicate that ZEA might have pro- and antiproliferative properties in prostate cancer cells, at concentrations 0.1 nM, 0.001 nM and 0.3 nM, 100 nM, respectively.

Topics: Apoptosis; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Membrane; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Fusarium; Humans; Male; Mitochondria; Prostatic Neoplasms; Toxicity Tests; Zearalenone

The 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5) is involved in estrogen and androgen metabolism. In our study we tested the influence of environmental hormones, such as phytoestrogens (flavonoids, coumarins, coumestans), on reductive and oxidative 17beta-HSD activity of the human 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5). These dietary substances were shown to be potent inhibitors of aromatase, different 17beta-HSDs and seem to play an important role in delay of development of hormone dependent cancers. Our studies show that reductive and oxidative activity of the enzyme are inhibited by many dietary compounds, especially zearalenone, coumestrol, quercetin and biochanin A. Among the group of flavones inhibitor potency is growing with increasing number of hydroxylations. We suggest that these substances are bound to the hydrophilic cofactor-binding pocket of the enzyme. An interesting inhibition pattern is observed for 18beta-glycyrrhetinic acid, which has no influence on the oxidative but only on the reductive reaction. This indicates that this substrate binds to pH- and cofactor-depending sites at the active center of the enzyme.

Topics: 17-Hydroxysteroid Dehydrogenases; Aromatase Inhibitors; Binding Sites; Breast Neoplasms; Coumestrol; Diet; Enzyme Inhibitors; Estrogens; Estrogens, Non-Steroidal; Female; Gene Expression; Genistein; Glycine max; Glycyrrhetinic Acid; Humans; Hydrogen-Ion Concentration; Hydroxylation; Isoenzymes; Isoflavones; Male; Models, Molecular; Oxidation-Reduction; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Quercetin; Recombinant Proteins; Testosterone; Zearalenone