Quinocetone induces mitochondrial apoptosis in HepG2 cells through ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/beta-catenin signaling pathway

摘要

Quinocetone (QCT) has been used as an animal feed additive in China since 2003. However, investigations indicate that QCT has potential toxicity due to the fact that it shows cytotoxicity, genotoxicity, hepatotoxicity, nephrotoxicity and immunotoxicity in vitro and animal models. Although QCTinduced mitochondrial apoptosis has been established, the molecular mechanism remains unclear. This study was aimed to investigate the role of voltage-dependent anion channel 1 (VDAC1) oligomerization and Wnt/beta-catenin pathway in QCT-induced mitochondrial apoptosis. The results showed VDAC inhibitor 4, 4-diisothiocyano stilbene-2, 2-disulfonic acid (DIDS) partly compromised QCT-induced cell viability decrease (from 34.1% to 68.5%) and mitochondrial apoptosis accompanied by abating VDAC1 oligomerization, cytochrome c (Cyt c) release and the expression levels of cleaved caspase-9, -3 and poly (ADP-ribose) polymerase (PARP). Meanwhile, overexpression VDAC1 exacerbated QCT-induced VDAC1 oligomerization and Cyt c release. In addition, lithium chloride (LiC1), an activator of Wnt/beta-catenin pathway, markedly attenuated QCT-induced mitochondrial apoptosis by partly restoring the expression levels of Wntl and beta-catenin. Finally, reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) obviously blocked QCT-induced VDAC1 oligomerization and the inhibition of Wntl /beta-catenin pathway. Taken together, our results reveal that QCT induces mitochondrial apoptosis by ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/beta-catenin pathway. (C) 2017 Elsevier Ltd. All rights reserved.