Quinones Derived from Polychlorinated Biphenyls Induce ROS-Dependent Autophagy by Evoking an Autophagic Flux and Inhibition of mTOR/p70S6k

Abstract

Autophagy is a "self-eating" destructive process that eliminates damaged organelles to maintain cellular homeostasis. Polychlorinated biphenyls (PCBs) are one of the most infamous industrial pollutants, which are ubiquitous in nature. In the present study, we found that an active, quinone-type PCB metabolite (PCB29-pQ) treatment causes an autophagic response through mTOR/p70S6k inhibition in HepG2 and MDA-MB-231 cells. Furthermore, our data suggested that PCB29-pQ enhances autophagosome formation through autophagic vacuole (AV) biogenesis, which evokes autophagic flux and induces AV-lysosome colocalization. The inhibition of autophagy enhanced PCB29-pQ-caused cytotoxicity, suggesting that autophagy serves as pro-survival machinery that plays a protective role in the early stage of PCB29-pQ-induced insult. However, higher concentration of PCB29-pQ exposure (>5 μM) caused autophagic cell death, which implied a shift from "pro-survival" to "pro-death" upon autophagic signaling. N-Acetylcysteine suppressed PCB29-pQ-induced autophagy and cytotoxicity, suggesting that ROS plays an important role in the regulation of PCB29-pQ-induced autophagy. Because autophagy shows significant implications in various human diseases and conditions, our current study provides a new mechanism for PCB-associated toxicity.

PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms

“…The evidence supporting this model includes: (1) PCB 95 increases mTOR phosphorylation in primary hippocampal cell cultures, and this effect is blocked by rapamycin; and (2) PCB 95-induced dendritic arborization is significantly inhibited by pharmacologic blockade of mTOR or the downstream signaling molecule 4EGI-1, and by siRNA knockdown of mTOR or the mTOR complex proteins, raptor and rictor. These data extend previous reports of PCB effects on mTOR signaling in hepatic cell lines (Hardesty et al 2017; Shi et al 2016), although in these studies Aroclor 1260 and a quinone metabolite of PCB 29 were observed to inhibit mTOR signaling. The reason(s) for the discrepant effects of PCBs on mTOR are not known but likely reflect differences with respect to the model systems (primary neurons vs. hepatic cell lines) and/or the PCB congeners investigated.…”

Mitigation of Nickel Toxicity and Growth Promotion in Sesame through the Application of a Bacterial Endophyte and Zeolite in Nickel Contaminated Soil

“…The results regarding reduced uptake of metal in the present study are in good agreement with [17,37]. Various researchers have also found that endophytes are capable of altering toxicity and availability of heavy metals to the plants through the production of siderophores and mobilization of organic acids and metal phosphates [18,87,90,92,94,95]. Moreover, microbial inoculation helps to enhance plants' ability to survive under stressful conditions [96].…”

“…Under abiotic stress, increased production of ROS in plants poses oxidative stress, resulting in inactivation of enzymes, nucleic acid damage, oxidation of protein, programmed cell death activation, and peroxidation of lipids [76,87]. To cope with oxidative stress, the plants actively secrete various types of AEs that regulate the stress condition to normal for optimum plant growth [88].…”

The quinone-based derivative, HMNQ induces apoptotic and autophagic cell death by modulating reactive oxygen species in cancer cells

“…They have been regarded as a tool for programmed cell death, and many of today’s anticancer agents aim at apoptosis as well as autophagy control [ 9 ]. Although quinone-related autophagy has not been reported as much as apoptosis, there are some papers that quinone derivatives induce ROS-dependent autophagy [ 52 , 53 ]. We therefore investigated whether HMNQ could also induce autophagy (Figure 4 ).…”