Quinocetone induces mitochondrial apoptosis in HepG2 cells through ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/β-catenin signaling pathway.
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 QCT-induced 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/β-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 (LiCl), an activator of Wnt/β-catenin pathway, markedly attenuated QCT-induced mitochondrial apoptosis by partly restoring the expression levels of Wnt1 and β-catenin. Finally, reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) obviously blocked QCT-induced VDAC1 oligomerization and the inhibition of Wnt1/β-catenin pathway. Taken together, our results reveal that QCT induces mitochondrial apoptosis by ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/β-catenin pathway.
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
Xiayun
X
Yang
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
Shusheng
S
Tang
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
Chongshan
C
Dai
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
Daowen
D
Li
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
Shen
S
Zhang
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
Sijun
S
Deng
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
Yan
Y
Zhou
Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China. Electronic address: xiaoxl@cau.edu.cn.
Xilong
X
Xiao
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011810:Quinoxalines / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D011810:Quinoxalines; D017382:Reactive Oxygen Species; C494762:VDAC1 protein, human; C495247:WNT1 protein, human; D051155:Wnt1 Protein; D051176:beta Catenin; C502851:quinocetone; D050995:Voltage-Dependent Anion Channel 1
Mitochondrial apoptosis; Quinocetone; Reactive oxygen species; VDAC1 oligomerization; Wnt1/β-catenin signaling