BNIP3 upregulation by ERK and JNK mediates cadmium-induced necrosis in neuronal cells.

Abstract

Cadmium (Cd) is a toxic heavy metal that may cause neurological disorders. We studied the mechanism underlying Cd-mediated cell death in neuronal cells. In Cd-induced neurotoxicity, caspase-3 was only modestly activated, and accordingly, zVAD-fmk, a pan-caspase inhibitor, partially attenuated cell death. However, pretreatment with Necrox-2 or Necrox-5, two novel necrosis inhibitors, suppressed cell death more markedly compared with pretreatment with zVAD-fmk. Moreover, the necrosis inhibitors did not prevent cleavage of caspase-3. These results indicate that caspase-independent necrosis is more prevalent in Cd-induced neurotoxicity. Bcl-2 and adenovirus E1B-19 kDa-interacting protein 3 (BNIP3) has been reported to be related to caspase-independent cell death. Cd treatment caused a dramatic upregulation of BNIP3 mRNA and protein levels in vitro and in vivo. Furthermore, knockdown of BNIP3 greatly inhibited Cd-induced cell death. Importantly, BNIP3 RNAi decreased lactate dehydrogenase release and the percentage of propidium iodide-positive cells, two markers of necrotic cell death due to rupture of the cell membrane, whereas it had no effect on activation of caspase-3 in Cd-treated cells. These data suggest that BNIP3 mediates caspase-independent necrosis, but not apoptosis. Moreover, our results indicate that induction of BNIP3 by Cd may not be related to HIF-1 which is generally regarded as a mediator responsible for BNIP3 expression. Finally, we show that mitogen-activated protein kinases (MAPKs) are activated by Cd in vitro and in vivo; ERK and JNK promote BNIP3 upregulation and subsequent necrosis. Taken together, our results suggest BNIP3, upregulated by activation of ERK and JNK, mediates Cd-induced necrosis in neuronal cells.

• Authors: Bin Wang, Jia-Li Xiao, Yi-Hui Ling, Xiao-Jing Meng, Bing Wu, Xin-Yi Yang, Fei Zou
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 140 Issue 2 Pg. 393-402 (Aug 01 2014) ISSN: 1096-0929 [Electronic] United States
• PMID: 24824807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• BNIP3 protein, human
• Hypoxia-Inducible Factor 1
• Membrane Proteins
• Proto-Oncogene Proteins
• Cadmium
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 4

Topics

• Animals
• Cadmium (toxicity)
• Cell Death (drug effects)
• Cell Line
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Hypoxia-Inducible Factor 1 (physiology)
• MAP Kinase Kinase 4 (metabolism)
• Male
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred BALB C
• Neurons (cytology, drug effects)
• Proto-Oncogene Proteins (physiology)
• Real-Time Polymerase Chain Reaction
• Up-Regulation