Cr(VI) induces ROS-mediated mitochondrial-dependent apoptosis in neuronal cells via the activation of Akt/ERK/AMPK signaling pathway
Journal
Toxicology in Vitro
Journal Volume
65
Date Issued
2020
Author(s)
Abstract
Hexavalent chromium (Cr(VI)), a well-known toxic industrial and environmental pollutant, has been shown to cause serious toxic and health effects. However, limited information is available on Cr(VI)-induced neurotoxic potential, with the underlying toxicological mechanisms remain mostly unclear. The present study demonstrated that the mitochondria-dependent apoptosis pathway was involved in Cr(VI)-induced SH-SY5Y cell (the human neuroblastoma cell line) death, which was accompanied by the appearance of cell shrinkage, increased mitochondrial membrane potential (MMP) depolarization and cytochrome c release, and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). Cr(VI) treatment also increased the generation of intracellular reactive oxygen species (ROS). Pretreatment of SH-SY5Y cells with antioxidant N-acetylcysteine (NAC) effectively attenuated ROS production and reversed these Cr(VI)-induced cytotoxicity and apoptotic responses. Furthermore, exposure to Cr(VI) significantly increased the phosphorylation levels of Akt, extracellular regulated kinase (ERK)1/2, and AMP-activated protein kinase (AMPK)α. NAC and the pharmacological inhibitor of Akt (LY294002), ERK1/2 (PD980590), and AMPKα (Compound C) markedly abrogated the Cr(VI)-induced activation of Akt, ERK1/2, and AMPKα signal, respectively, with the concomitant inhibition of mitochondrial dysfunction and caspase activation. Additionally, all these inhibitors suppressed Cr(VI)-induced phosphorylation of Akt, ERK1/2, and AMPKα and of each other. Collectively, these results suggest that Cr(VI) exerts its cytotoxicity on neuronal cells by inducing mitochondria-dependent apoptosis through the interdependent activation of Akt, ERK1/2, and AMPKα, which are mainly mediated by ROS generation. ? 2020 Elsevier Ltd
Subjects
Akt; AMPKα; Apoptosis; ERK1/2; Hexavalent chromium (Cr(VI)); Neurotoxicity; Reactive oxygen species
SDGs
Other Subjects
2 morpholino 8 phenylchromone; acetylcysteine; ascorbic acid; caspase 3; caspase 7; chromium; compound C; cytochrome c; hexavalent chromium; hydroxymethylglutaryl coenzyme A reductase kinase; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase inhibitor; pd 980590; protein kinase B; protein serine threonine kinase inhibitor; reactive oxygen metabolite; unclassified drug; chromium; chromium hexavalent ion; hydroxymethylglutaryl coenzyme A reductase kinase; mitogen activated protein kinase; protein kinase B; reactive oxygen metabolite; antioxidant activity; Article; cell shrinkage; cellular parameters; controlled study; cytotoxicity; enzyme activation; enzyme phosphorylation; enzyme release; human; human cell; mitochondrial membrane potential; mitochondrion; neuroapoptosis; neurotoxicity; oxidative stress; SH-SY5Y cell line; signal transduction; apoptosis; drug effect; metabolism; mitochondrion; nerve cell; physiology; signal transduction; tumor cell line; AMP-Activated Protein Kinases; Apoptosis; Cell Line, Tumor; Chromium; Extracellular Signal-Regulated MAP Kinases; Humans; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction
Publisher
Elsevier Ltd
Type
journal article