Journal
METALLOMICS
Volume 13, Issue 7, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/mtomcs/mfab042
Keywords
Cadmium; caspase-8; Fas; JNK; mitochondrial apoptotic pathway; neuron
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Funding
- National Natural Science Foundation of China [31772808, 31872533, 31702305]
- National Key Research and Development Program of China [2016YFD0501208]
- Excellent Young Teachers Program of Yangzhou University
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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This study demonstrates that in rat cerebral cortical neurons, the mechanisms underlying Cd-induced Fas-mediated activation of the mitochondrial apoptotic pathway involve the activation of caspase-8 and the c-Jun N-terminal kinase (JNK) pathway.
Cadmium (Cd) is a toxic metal and an environmental pollutant and can cause neurotoxicity by inducing apoptosis. Fas (CD95/Apo-1) is a cell-surface receptor that triggers apoptosis upon ligand binding, mediated through the mitochondrial apoptotic pathway. However, the role and regulatory mechanism of Fas in Cd-induced neuronal apoptosis remain understudied. Here, we demonstrate that activation of caspase-8 and the c-Jun N-terminal kinase (JNK) pathway are mechanisms underlying Cd-induced Fas-mediated activation of the mitochondrial apoptotic pathway in rat cerebral cortical neurons. In vitro, Cd induced apoptosis in primary cortical neurons by activating caspase-8, JNK, and the mitochondrial apoptotic pathway. Fas knockdown enhanced cell viability in the presence of Cd and inhibited apoptosis by blocking Cd-activated Fas, caspase-8, and JNK. Fas knockdown also inhibited the decrease of mitochondrial membrane potential, cleavage of caspase-9/3 and poly (ADP-ribose) polymerase 1, and impaired nuclear translocation of apoptosis-inducing factor and endonuclease G. In vivo, Fas knockdown alleviated Cd-induced neuronal injury and inhibited apoptosis, activation of caspase-8, JNK, and mitochondrial apoptotic pathways in rat cerebral cortical neurons. In summary, our results demonstrate that Cd-activated Fas relays apoptotic signals from the cell surface to the mitochondria via caspase-8 and JNK activation in rat cerebral cortical neurons, leading to aggravation of the neuronal injury.
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