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

•α-Zearalenone and β-zearalenol trigger ER stress in human colorectal cancer cells (HCT116).•α-Zearalenone and β-zearalenol induce apoptosis via activation of the mitochondrial pathway.•Quercetin protect cells against α/β-zearalenol-induced ER stress and apoptosis.

Zearalenone (ZEN) and its metabolites are found in many food products and are known to induce many toxic effects. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-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 α-ZOL and β-ZOL-induced toxicity in HCT116 cells. We showed that cell treatment with α-ZOL/β-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 (ΔΨm), a downstream generation of O2•− and caspase 3 activation. Cellular deficiency of the pro-apoptotic proteins Bax and Bak protected cells against α/β-ZOL-induced toxicity. However, treatment with α-ZOL or β-ZOL combined with Quercetin (QUER), a common dietary flavonoid with well-known antioxidant activity, significantly reduced damage induced by α and β-ZOL in all tested markers. We concluded that QUER protects against the cellular toxicity of α and β-ZOL.×