BNIP3 upregulation by ERK and JNK mediates cadmium-induced necrosis in neuronal cells.
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.
Department of Occupational Heath and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China feizou58@163.com.
Bin
B
Wang
Department of Occupational Heath and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China feizou58@163.com.
Jia-Li
JL
Xiao
Department of Occupational Heath and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China feizou58@163.com.
Yi-Hui
YH
Ling
Department of Occupational Heath and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xiao-Jing
XJ
Meng
Department of Occupational Heath and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
Bing
B
Wu
Department of Occupational Heath and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xin-Yi
XY
Yang
Department of Occupational Heath and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China feizou58@163.com.
Fei
F
Zou
D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
C090121:BNIP3 protein, human; D051793:Hypoxia-Inducible Factor 1; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D002104:Cadmium; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4
BNIP3; MAPK; cadmium; cell death