2,4,6-Trinitrotoluene Induces Apoptosis via ROS-Regulated Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in HepG2 and Hep3B Cells

Abstract

2,4,6-trinitrotoluene (TNT) has been reported to cause numerous adverse effects. However, the detailed molecular mechanisms underlying TNT-induced liver toxicity need to be elucidated. In this study, we used HepG2 (p53wt) and Hep3B (p53null) cell lines to investigate the cytotoxic effects of TNT. At first, we found that TNT significantly decreased cell viability and induced DNA damage. Thereafter, through transcriptomic analysis, we observed that the diverse biological functions affected included mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondrial dysfunction was evidenced by the loss of mitochondrial membrane potential, increased expression of cleaved-caspase-9&-3 and increased caspase-3/7 activity, indicating that apoptosis had occurred. In addition, the expressions of some ER stress-related proteins had increased. Next, we investigated the role of reactive oxygen species (ROS) in TNT-induced cellular toxicity. The levels of DNA damage, mitochondrial dysfunction, ER stress and apoptosis were alleviated when the cells were pretreated with N-acetyl-cysteine (NAC). These results indicated that TNT caused the ROS dependent apoptosis via ER stress and mitochondrial dysfunction. Finally, the cells transfected with CHOP siRNA significantly reversed the TNT-induced apoptosis, which indicated that ER stress led to apoptosis. Overall, we examined TNT-induced apoptosis via ROS dependent mitochondrial dysfunction and ER stress in HepG2 and Hep3B cells.

Gecko Active Components Regulates Endoplasmic Reticulum Stress to Induce the Apoptosis of KYSE150 Cells through PERK Pathway

“…In the present study, we demonstrated that GACs could significantly inhibit the proliferation of KYSE150 cells in a dose-and time-dependent manners via MTT assay, and we found that GACs induces apoptosis in ESCC cells via ROS generation, calcium production, and mitochondrial dysfunction, meanwhile ERs is activated by ROS generation. Previous studies have found that cancer cells contain higher levels of ROS than those of normal cells as a result of their hypermetabolism, which is closely associated with cell proliferation, differentiation and cell death [12] [13] [14]. Our results showed that GACs increased ROS levels of KYSE150 cells in a time-dependent manner.…”

Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia

“…The current study demonstrated that the hypoxic situation in placenta under PE can induce trophoblastic cell apoptosis directly by the examination of apoptosis‐related protein expression and other analysis by using PE animal models and cultured trophoblastic cells under hypoxia in vitro. Apoptosis can be induced by the activation of death receptors, mitochondrial dysfunction, DNA damage, and ER stress . In addition, excessive ER stress has been observed in pregnancies complicated by diabetes in late gestation, intrauterine growth restriction, and PE .…”

Connexin32 plays a crucial role in ROS-mediated endoplasmic reticulum stress apoptosis signaling pathway in ischemia reperfusion-induced acute kidney injury

“…Many researches had already showed that ROS played an essential role in decision of cell destiny: death or survival in some pathological process, including I/R injury [ 40 , 41 ]. ROS could initiate the cascade of cell damage, apoptosis/necrosis, and pro-inflammatory responses, also could trigger cell apoptosis through various signaling pathways, such as inflammation, oxidative stress or ERS response [ 42 , 43 ]. Recently, studies had shown that ROS destroyed ER function and initiated UPR and ERS in vivo and vitro, which might be an important mechanism that lead to tissues damage and cell apoptosis [ 44 , 45 ].…”