Alpha-naphthoflavone induces apoptosis through endoplasmic reticulum stress via c-Src-, ROS-, MAPKs-, and arylhydrocarbon receptor-dependent pathways in HT22 hippocampal neuronal cells

•α-Naphthoflavone (αNF), an arylhydrocarbon receptor modulator (AhR), induces apoptosis in HT22 hippocampal neuronal cells.•ER stress plays a role in αNF-induced apoptosis.•The c-Src-, ROS-, MAPK-, and AhR-dependent pathways are implicated in αNF-induced ER stress and apoptosis.•The AhR nuclear tran...

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Bibliographic Details
Published in:Neurotoxicology (Park Forest South) 2019-03, Vol.71, p.39-51
Main Authors: Yu, Ah-Ran, Jeong, Yeon Ju, Hwang, Chi Yeon, Yoon, Kyung-Sik, Choe, Wonchae, Ha, Joohun, Kim, Sung Soo, Pak, Youngmi Kim, Yeo, Eui-Ju, Kang, Insug
Format: Article
Language:English
Subjects:
Accumulation
Acetylcysteine
Animals
Antioxidants
Apoptosis
Aromatic compounds
Aryl hydrocarbon receptor modulator
Benzoflavones - metabolism
Caspase
Caspase-12
CCAAT/enhancer-binding protein
Cell activation
Cell death
Cell Line
Cytotoxicity
Endoplasmic reticulum
Endoplasmic Reticulum Stress
Enzyme inhibitors
ER stress
Extracellular signal-regulated kinase
Hippocampus
Hippocampus - metabolism
Homology
HT22 hippocampal neuronal cells
Inhibition
Inhibitors
Kinases
MAP kinase
Mice
Mitogen-Activated Protein Kinases - metabolism
Molecular modelling
Mortality
Naphthoflavone
Neurons - metabolism
Phosphorylation
Proteins
Proto-Oncogene Proteins pp60(c-src) - metabolism
Reactive Oxygen Species
Receptors, Aryl Hydrocarbon - metabolism
Signal Transduction
siRNA
Src protein
Stress
Transcription
Transfection
α-Naphthoflavone
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Summary:•α-Naphthoflavone (αNF), an arylhydrocarbon receptor modulator (AhR), induces apoptosis in HT22 hippocampal neuronal cells.•ER stress plays a role in αNF-induced apoptosis.•The c-Src-, ROS-, MAPK-, and AhR-dependent pathways are implicated in αNF-induced ER stress and apoptosis.•The AhR nuclear translocator-dependent genomic pathway also mediates αNF-induced ER stress and apoptosis. α-Naphthoflavone (αNF) is a prototype flavone, also known as a modulator of aryl hydrocarbon receptor (AhR). In the present study, we investigated the molecular mechanisms of αNF-induced cytotoxic effects in HT22 mouse hippocampal neuronal cells. αNF induced apoptotic cell death via activation of caspase-12 and -3 and increased expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by treatment with the ER stress inhibitor, salubrinal, or by CHOP siRNA transfection reduced αNF-induced cell death. αNF activated mitogen-activated protein kinases (MAPKs), such as p38, JNK, and ERK, and inhibition of MAPKs reduced αNF-induced CHOP expression and cell death. αNF also induced accumulation of reactive oxygen species (ROS) and an antioxidant, N-acetylcysteine, reduced αNF-induced MAPK phosphorylation, CHOP expression, and cell death. Furthermore, αNF activated c-Src kinase, and inhibition of c-Src by a kinase inhibitor, SU6656, or siRNA transfection reduced αNF-induced ROS accumulation, MAPK activation, CHOP expression, and cell death. Inhibition of AhR by an AhR antagonist, CH223191, and siRNA transfection of AhR and AhR nuclear translocator reduced αNF-induced AhR-responsive luciferase activity, CHOP expression, and cell death. Finally, we found that inhibition of c-Src and MAPKs reduced αNF-induced transcriptional activity of AhR. Taken together, these findings suggest that αNF induces apoptosis through ER stress via c-Src-, ROS-, MAPKs-, and AhR-dependent pathways in HT22 cells.
ISSN:0161-813X
1872-9711
DOI:10.1016/j.neuro.2018.11.011