Activation of ER stress and apoptosis by α- and β-zearalenol in HCT116 cells, protective role of Quercetin

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.