Cadmium-induced apoptosis in neuronal cells is mediated by Fas/FasL-mediated mitochondrial apoptotic signaling pathway

Yan Yuan,Hui Zou,Shiwen Zhao,Jinlong Yang,Jianchun Bian,Jianhong Gu,Yajing Zhang,Xuezhong Liu,Zongping Liu,Yi Wang,Jie Chen,Tao Wang

doi:10.1038/s41598-018-27106-9

Yan Yuan, Hui Zou + Show 10 more

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https://doi.org/10.1038/s41598-018-27106-9

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Journal: Scientific Reports	Publication Date: Jun 11, 2018
Citations: 67	License type: open-access

Affiliation: Yangzhou University

Abstract

Cadmium (Cd) is a toxic metal capable of damaging brain. Studies have demonstrated that Cd can induce apoptosis in neuronal cells. The CD95/APO-1 (Fas)/Fas Ligand (FasL) signaling pathway is one of the primary apoptosis pathways, but the role and regulatory mechanism of this pathway in neuronal cells remain unclear. Here, we demonstrated the underlying mechanism of the Fas/FasL system involving the mitochondrial apoptotic pathway in neuronal cells. Primary rat cerebral cortical neurons and PC12 cells were exposed to Cd, which significantly activated expression of Fas, FasL, Fas-associated death domain (FADD) and cleaved caspase-8. However, expression of cleaved caspase-8 decreased at 20 µM Cd in primary cerebral cortical neurons. Importantly, Cd-induced apoptotic morphological changes and increase in the apoptosis rate were partially blocked by Z-IETD-FMK, which is a specific inhibitor of caspase-8. Cd-mediated increase of apoptosis rate was inhibited by anti-FasL antibody. Furthermore, our data revealed that Z-IETD-FMK also blocked increase of truncated BH3 interacting domain death agonist (tBID)/BID, decrease of the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associate X protein (Bax) ratio and mitochondrial membrane potential (MMP), release of cytochrome c, as well as cleavage of caspase-9/3 and poly (ADP-ribose) polymerase (PARP) induced by Cd. Taken together, our results demonstrate that the Fas/FasL-mediated mitochondrial apoptotic pathway plays an important role in Cd-induced neuronal apoptosis.

Highlights

Cadmium (Cd) is a toxic heavy metal with common exposure in environmental and industrial pollutant
In our previous report[18,19], we demonstrated that neuronal apoptosis induced by Cd is associated with activation of the mitochondrial apoptotic pathway by decreasing mitochondrial membrane potential (MMP) and the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein (Bax) ratio, as well as activating caspase-9, caspase-3, and Poly (ADP-ribose) polymerase (PARP) in primary rat cerebral cortical neurons and PC12 cells
10 μM Cd induced activation of Fas, Fas ligand (FasL), Fas-associated death domain (FADD), and caspase-8 within 24 h. These findings clearly indicate that Cd activates Fas/ FasL signaling pathways in neuronal cells

Summary

Introduction

Cadmium (Cd) is a toxic heavy metal with common exposure in environmental and industrial pollutant. The extrinsic pathway is initiated by binding of cytokine ligands such as Fas ligand (FasL) and TNF to the death receptors such as CD95/APO-1 (Fas) and TNF receptors This is followed by caspase-8 activation, which in turn either directly activates caspase-3 or merges with the mitochondrial pathway via cleavage of the Bcl-2 family member, p22 BID12. Both pathways converge on activation of caspase-3 which leads to cell death[13,14]. The underlying mechanism of the Fas/FasL apoptotic pathway in neuronal cells remains unclear. The underlying mechanism of the Fas/FasL system involving the mitochondrial apoptotic pathway in neuronal cells remains unclear. The aim of this study was to investigate the role of the Fas/FasL system in Cd-induced neuronal apoptosis and to understand better the relationship between mitochondrial and Fas/FasL apoptotic signaling pathways

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