Induction of mitochondrial apoptosis pathway mediated through caspase-8 and c-Jun N-terminal kinase by cadmium-activated Fas in rat cortical neurons.

Shuangquan Wen, Li Wang, Wenhua Zhang, Mingchang Xu, Ruilong Song, Hui Zou, Jianhong Gu, Jianchun Bian, Yan Yuan, Zongping Liu

Metallomics : integrated biometal science 2021 Jul 12

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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. The Author(s) 2021. Published by Oxford University Press.

Citation

Shuangquan Wen, Li Wang, Wenhua Zhang, Mingchang Xu, Ruilong Song, Hui Zou, Jianhong Gu, Jianchun Bian, Yan Yuan, Zongping Liu. Induction of mitochondrial apoptosis pathway mediated through caspase-8 and c-Jun N-terminal kinase by cadmium-activated Fas in rat cortical neurons. Metallomics : integrated biometal science. 2021 Jul 12;13(7)