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

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.

The Effect of Interval Training with Selenium Consumption on Gene Expression of Caspase- 3 and Cyclin-D in Liver Tissue of Cadmium-Exposed Rats

“…Cadmium can cause cell damage and apoptosis in various organs of the body, including the liver, kidneys and the heart (11), which conforms to results of this research. Also, cadmium as one of the heavy metals and environmental pollutants contributes to the induction of the Fas/Fals signal pathway and plays an important role in increasing caspase-3 (12), which is consistent with the results of this study. Also, a study reported that cadmium in the nano-molar range could increase cyclin-D and cell proliferation of the anterior pituitary tissue (13), which is not consistent with the results of this study.…”

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

“…Once taken into the body, cadmium accumulates in the kidney and liver and has an extremely long half-life of 20-40 years [330][331][332] . Chronic cadmium exposure is associated with hypertension, kidney dysfunction, bone demineralization, and neurological diseases [333][334][335][336][337] . Cadmium is known to cross the blood-brain barrier and eventually accumulate in the brain, leading to neurotoxicity [338] .…”

“…Cadmium is known to cross the blood-brain barrier and eventually accumulate in the brain, leading to neurotoxicity [338] . In the brain, cadmium induces activation of various signaling pathways involved in inflammation, oxidative stress, and neuronal apoptosis [339,340,337] .…”

Niban protein regulates apoptosis in HK-2 cells via caspase-dependent pathway

“…Overexpression of Niban down-regulated the level of cleaved-caspase 8, cleaved-caspase 9, a-SMA, and apoptosis, while up-regulated the levels of E-cadherin. Among them caspase 8 and caspase 9 are involved in the Fas/FasL pathway and the mitochondrial stress pathway, respectively, and are marker proteins on these two apoptotic pathways [16,31]. These findings indicated that Niban may inhibit apoptosis in HK-2 cells through caspase-dependent pathway, which is mainly related to the Fas/FasL pathway and the mitochondrial stress pathway.…”

“…In order to evaluate the role of Niban in regulating the apoptosis of HK-2 cells, we further examined the marker proteins cleaved-caspase 8, cleaved-caspase 9, and cleaved-caspase 12 in three classical apoptotic pathways induced by AngII, including the Fas/FasL pathway, the mitochondrial stress pathway, and ER stress pathway, respectively [15][16][17]. As shown in Figure 6, the expression levels of cleaved-caspase 8 and cleaved-caspase 9 were increased after stimulation with AngII (p < .05).…”