Apoptosis induced by Trimethyltin chloride in human neuroblastoma cells SY5Y is regulated by a balance and cross-talk between NF-κB and MAPKs signaling pathways

Abstract

Trimethyltin chloride (TMT) has been known as a classic neurotoxicant which can cause serious neuronal degeneration diseases. Nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways play pivotal role in the central nerves system. In the present study, the intracellular pathways involved in TMT-induced apoptosis on human neuroblastoma cells SY5Y (SH-SY5Y) were investigated. We observed high level of nuclear NF-κB p65 submit, activated JNK, ERK, and p38 by TMT exposure. In contrast, low level of Bcl-2 and XIAP (two known NF-κB-regulated endogenous anti-apoptotic molecules) was present. To further investigate the role of these pathways and the relationship between them, specific inhibitors were used and the alteration of each pathway was evaluated. Pretreatment with MG132, an inhibitor of proteasome activity, and BAY11-7082, an inhibitor of IκBα phosphorylation, both inhibited NF-κB p65 translocation and significantly promoted apoptosis. NF-κB inhibition also induced down-expression of Bcl-2 and XIAP, exaggerated JNK phosphorylation, and ERK inhibition. SP600125 and U0126, by blocking the phosphorylation of c-Jun and MEK1/2, inhibited JNK and ERK phosphorylation, respectively, and attenuated apoptosis significantly. JNK and ERK inhibition also induced IκBα degradation and NF-κB p65 translocation, leading to expression of Bcl-2 and XIAP. The detrimental role of MG132 and BAY11-7082 appears related to the exaggerated JNK phosphorylation. The SP600125 and U0126 neuroprotection appears related to NF-κB-regulated transcriptional control of Bcl-2 and XIAP. These results suggest that the cross-talk and a balance between NF-κB and MAPKs may be involved in TMT-induced apoptosis on SH-SY5Y cells.

Artocarpin, an isoprenyl flavonoid, induces p53-dependent or independent apoptosis via ROS-mediated MAPKs and Akt activation in non-small cell lung cancer cells

“…Recent studies have demonstrated that ROS-dependent NF-kB activation induced the protein expression of c-Myc and Noxa in p53-independent human NSCLC cell death [50]. On the contrary, NF-kB activation was involved in resistance to oxidative stress and p53-mediated programmed cell death [51–53]. Therefore, we investigated whether this transcription factor may play a role in artocarpin-induced apoptosis.…”

“…Evaluation of apoptosis was performed using an Annexin-V-FITC/propidum iodide (PI) apoptosis kit as described previously [51]. Following treatment with artocarpin with or without inhibitors, cells were labeled with Annexin-V and PI, and then evaluated by a flow cytometer.…”

Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice

“…In a model of TMT-induced neurodegeneration, Casalbore et al (2010) showed that phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 activation, triggered by BDNF overexpression, attenuated the TMT-induced neurotoxicity in NSCs. In contrast, a recent study by Qing et al (2013) reported that pre-treatment with the MEK-ERK1/2 inhibitor U0126 reduced TMT-induced apoptosis in human neuroblastoma SY5Y cells via upregulation of survival factors, Bcl-2 and XIAP, suggesting that ERK signaling may play a role in neuronal cell death. In the present study, we observed that ERK1/2 was markedly activated in the mouse hippocampus following TMT treatment, although the temporal expression tendency was differently observed within each subregions of the hippocampus.…”

Inhibition of NF-κB promotes autophagy via JNK signaling pathway in porcine granulosa cells

“…We hypothesized that this process might involve crosstalk between NF-kB and the JNK signaling pathway. In the human neuroblastoma cell line SY5Y, NF-kB inhibition exaggerated the phosphorylation of JNK mediated by trimethyltin chloride [26]. Gancz et al reported that p65 silencing by RNAi abrogated complement-induced JNK activation in HeLa cells [27].…”