Activation of ER stress and apoptosis by α- and β-zearalenol in HCT116 cells, protective role of Quercetin
Activation of ER stress and apoptosis by α- and β-zearalenol in HCT116 cells, protective role of Quercetin
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DOI：
10.1016/j.neuro.2015.11.004
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发表时间：
2016-03-01
期刊：
影响因子：
3.4
通讯作者：
Abid-Essefi, Salwa
中科院分区：
文献类型：
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作者：
Ben Salem, Intidhar;Prola, Alexandre;Abid-Essefi, Salwa
玉米赤霉烯酮（ZEN）及其代谢物存在于许多食品中，并且已知会引起许多毒性作用。ZEN的主要代谢产物是α -玉米醛烯醇（α - zol）和β -玉米醛烯醇（β - zol）。它们介导细胞毒性作用的机制尚不清楚，似乎因细胞类型而异。我们研究了α - zol和β - zol诱导HCT116细胞毒性的可能潜在机制。我们发现，用α - zol / β - zol处理细胞会产生内质网（ER）应激，并激活未折叠蛋白反应（UPR），这可以通过XBP1 mRNA剪接和GADD34、GRP78、ATF4和CHOP的上调来证明。凋亡是由ZEN代谢物诱导的内质网应激触发的，并通过线粒体依赖途径进行，其特征是线粒体跨膜电位（Delta psi(m)）的丧失、下游O-2（中心点-）和caspase 3的激活。细胞缺乏促凋亡蛋白Bax和Bak可保护细胞免受α / β - zol诱导的毒性。然而，用α - zol或β - zol联合槲皮素（QUER）（一种众所周知具有抗氧化活性的常见膳食类黄酮）治疗，可显著降低α和β - zol对所有测试标志物的损伤。我们得出结论，QUER对α和β - zol的细胞毒性有保护作用。x (C) 2015 Elsevier Inc.版权所有。
Zearalenone (ZEN) and its metabolites are found in many food products and are known to induce many toxic effects. The major ZEN metabolites are alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL). The mechanisms by which they mediate their cytotoxic effects are not well known and seem to differ depending on the type of cells. We investigated the possible underlying mechanism in alpha-ZOL and beta-ZOL-induced toxicity in HCT116 cells. We showed that cell treatment with alpha-ZOL/beta-ZOL generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of GADD34, GRP78, ATF4 and CHOP. Apoptosis was triggered by ZEN metabolites-induced ER stress, and executed through a mitochondria-dependent pathway, characterized by a loss of mitochondrial transmembrane potential (Delta psi(m)), a downstream generation of O-2(center dot-) and caspase 3 activation. Cellular deficiency of the pro-apoptotic proteins Bax and Bak protected cells against alpha/beta-ZOL-induced toxicity. However, treatment with alpha-ZOL or beta-ZOL combined with Quercetin (QUER), a common dietary flavonoid with well-known antioxidant activity, significantly reduced damage induced by alpha and beta-zoL in all tested markers. We concluded that QUER protects against the cellular toxicity of alpha and beta-ZOL.x (C) 2015 Elsevier Inc. All rights reserved.