Estrogen Receptor α Is Crucial in Zearalenone-Induced Invasion and Migration of Prostate Cancer Cells

Kowalska, Karolina; Habrowska-Górczyńska, Dominika Ewa; Urbanek, Kinga Anna; Domińska, Kamila; Piastowska-Ciesielska, Agnieszka Wanda

doi:10.3390/toxins10030098

Cited by 40 publications

(32 citation statements)

References 34 publications

(49 reference statements)

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“…Our previous results showed that ZEA might induce both apoptosis and proliferation in PC3 cells, expressing both ERs [16]. Based on our research, it seems that ERα is necessary for the ZEA-induced proliferation of cells [17], while ERβ might play a contradictory role. In this study, for the first time, we showed that ZEA in high doses induces oxidative stress in PCa cells, which is linked with DNA damage and cell cycle arrest in the G2/M cell cycle phase.…”

Section: Discussionmentioning

confidence: 51%

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

Kowalska

Habrowska-Górczyńska

Domińska

et al. 2020

Toxins

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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.

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Section: Discussionmentioning

confidence: 51%

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

Kowalska

Habrowska-Górczyńska

Domińska

et al. 2020

Toxins

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“…ER activity regulates the Wnt/β-catenin and TGF-β pathways [21,22]. ZEN is known to alter the balance between ER, Wnt/β-catenin and TGF-β signaling in prostatic cancer cells as well as ovarian cells, these being linked with the pro-proliferative and cancerogenic effects of ZEN [31,32]. Here, we demonstrate that ZEN induces an accumulation of ERα, but no ERβ, in the intestine, and modulates the Wnt/β-Catenin and TGFβ signaling pathways in the intestine.…”

Section: Discussionmentioning

confidence: 99%

Section: Key Contributionmentioning

confidence: 99%

“…Taken together, these results suggest that ZEN can induce transient proliferation in the small intestinal crypt, which could be connected with pro-cancerogenic changes in wingless-type MMTV integration site family (Wnt)/β-catenin and transforming growth factor β (TGF-β) signaling pathways. The two latter pathways are known to play a key role in the toxic effect of ZEN in ovarian [31], uterine [31] and prostatic cancer cells [32], and to be implicated in the onset and progression of intestinal proliferative/cancerous events [33], but the activation of these pathways by ZEN has not been investigated to date.In this study, we investigated the activation/repression of Wnt/β-catenin and TGF-β signaling pathways, the immune status and metabolism by ZEN to understand the effect of this toxin on the intestine of castrated male pigs. Our results confirmed that the small intestine is a target for ZEN, and that its toxic effect could contribute to the development or aggravation of severe intestinal pathologies such as cancer.…”

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confidence: 99%

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Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

Lahjouji

Bertaccini

Neves

et al. 2020

Toxins

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The mycotoxin zearalenone (ZEN), which frequently contaminates cereal-based human food and animal feed, is known to have an estrogenic effect. The biological response associated with exposure to ZEN has rarely been reported in organs other than the reproductive system. In the intestine, several studies suggested that ZEN might stimulate molecular changes related to the activation of early carcinogenesis, but the molecular mechanisms behind these events are not yet known. In this study, we investigated gene expression and changes in protein abundance induced by acute exposure to ZEN in the jejunum of castrated male pigs using an explant model. Our results indicate that ZEN induces the accumulation of ERα but not ERβ, modulates Wnt/β-catenin and TGF-β signaling pathways, and induces molecular changes linked with energy sensing and the antimicrobial activity without inducing inflammation. Our results confirm that the intestine is a target for ZEN, inducing changes that promote cellular proliferation and could contribute to the onset of intestinal pathologies. Key Contribution:The consequences of the estrogen-disrupting activity of ZEN in the small intestine were investigated. Our results indicate that acute exposure to ZEN promotes changes in signaling pathways that are important for the intestinal physiology such as estrogen, Wnt/β-catenin and TGF-β as well as changes in the expression of metabolic sensing molecules and antimicrobial proteins.ZEN is more dependent on the activation of the estrogen receptor (ER) signaling pathway, which has an anti-inflammatory [8,11,12], anti-apoptotic and proliferating effect [3,13,14]. ER is a ligand-activated transcriptional factor, and signaling is mainly activated directly upon DNA binding in the estrogen response elements located in target genes, but also indirectly (not involving DNA binding) through interaction with other signaling pathways [15][16][17]. There are two types of ERs, ERα and ERβ, whose roles differ. ERα is the main regulator of estrogen-dependent genes and its activation has proliferative effects. ERβ, when co-expressed with ERα, tends to restrain ERα activity and its activation inhibits cell proliferation [18]. ZEN can activate both ERs but is a partial agonist of ERβ and a full agonist of ERα [19]. Consequently, the biological response to exposure to ZEN varies depending on the tissue-specific ratio of the ER α vs. β, as well as on the density of these receptors [20]. In the intestine, the presence of each ER is distributed differently along the crypt-villus axis, ERα being more abundant in the crypt (where cell proliferation occurs) while ERβ is more abundant in the villi (composed of differentiated enterocytes) [21,22]. Estrogen signaling interacts with other pathways that are important for intestinal homeostasis and its disruption seems to relate to the development of chronic intestinal diseases and cancer [23][24][25]. As the intestine is an estrogen-responding organ, it is important to understand the molecular effect of natural endocrine disruptors suc...

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“…Of Fusarium derived mycotoxins, trichothecene deoxynivalenol (DON) has been shown to cause emesis and to inhibit protein biosynthesis (Beasley 2017;EFSA and Knudsen 2017). Zearalenone (ZEN) is known for its ability to bind to the estrogen receptor (Kowalska et al 2018). Ochratoxin A (OTA) critically affects the kidney due to accumulation in the nephron (Malir et al 2013), while exposure to fumonisins has been linked to esophageal cancer (Shirima et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal assessment of mycotoxin co-exposures in exclusively breastfed infants

Braun

Schernhammer

Marko

et al. 2020

Preprint

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Early-life development of infants may be critically affected by man-made or natural contaminants including mycotoxins. However, data on the occurrence of food contaminants in breast milk is scarce and prohibits a comprehensive exposure and risk assessment for mothers and their infants. Here, we present a longitudinal exposure assessment over the first 211 days of a single newborn girl (study A) by measuring multiple mycotoxins in milk. Eighty-seven consecutive breast milk samples were obtained from the newborn's mother living in Austria and following a regular mixed local diet. Mycotoxins were analyzed by utilizing a highly sensitive LC-MS/MS approach covering 29 mycotoxins and key metabolites. In addition to this longitudinal study, three mothers provided breast milk samples each on five consecutive days, for a preliminary comparison of inter-day and inter-individual variation in exposures (study B). Study A revealed that mycotoxin occurrence in breast milk was limited to the emerging mycotoxins alternariol monomethyl ether (AME), beauvericin (BEA), enniatins (A, A1, B, B1) and to ochratoxin A (OTA), which is regulated in commercial infant food. These mycotoxins were, if present, mostly detected at very low concentrations (<10 ng/L), except AME which exceeded this concentration on two distinct days by a factor of 3x and 5x. Overall, longitudinal results indicated chronic low-dose exposure to the detected mycotoxins. Other regulated mycotoxins including the carcinogenic aflatoxins or the estrogenic zearalenone and their biotransformation products were absent in all tested samples. Study B confirmed the results of study A, with minimal inter-day and inter-individual variation. Based on the data set obtained in study A, exposure of the infant was estimated. Exposure estimates of individual mycotoxins were on average below 1 ng/kg body weight per day. Our findings suggest that exposure to mycotoxins in Austrian breast milk may be negligible. Recommended maximum daily intake levels were clearly not exceeded. However, exposure is likely to be higher in populations with lower food safety standards. In the light of co-occurrence of several emerging mycotoxins in breast milk, future studies should address lowdose mixture effects. This also includes other environmental contaminants which may be present in this bio-fluid and should involve an exposome-scale risk assessment. All these efforts must be intended to minimize exposure of mothers and infants in a window of high susceptibility.

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Estrogen Receptor α Is Crucial in Zearalenone-Induced Invasion and Migration of Prostate Cancer Cells

Cited by 40 publications

References 34 publications

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

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

Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

Longitudinal assessment of mycotoxin co-exposures in exclusively breastfed infants

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