The essential role of ERK in 4-oxo-2-nonenal-mediated cytotoxicity in SH-SY5Y human neuroblastoma cells.
Lipid peroxidation byproducts, such as 4-hydroxynonenal (HNE) and 4-oxo-2-nonenal (ONE), induce cell death in a wide variety of cell types, partly by modulating intracellular signaling pathways. However, the specific mechanisms involved, particularly for ONE, are unclear while c-Jun N-terminal kinase (JNK) has been shown to be essential in HNE-mediated cytotoxicity. In this study, we examined the role of mitogen-activated protein kinases signaling pathways in ONE-induced cytotoxicity in SH-SY5Y human neuroblastoma cells and found that ONE strongly induces the phosphorylation of extracellular signal-regulated kinase (ERK) and JNK, but not p38 MAPK. Interestingly, a transient exposure of the cells to ONE resulted in cell death, which contrasts with HNE-mediated toxicity. Importantly, blocking the ERK pathway, but not the JNK pathway, protected cells against ONE-induced cytotoxicity indicating a striking difference between the ONE- and HNE-mediated cytotoxicity mechanisms. Furthermore, inhibition of ERK reduced ONE-induced phosphorylation of p53, a key modulator of the cellular stress response, and the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), a hallmark of apoptosis. Overall, these data strongly suggest that ERK plays an essential role in ONE-mediated cytotoxicity and that ERK is an upstream component of p53-mediated apoptosis.
Lee
Hyun-Pil
HP
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
Zhu
Xiaochun
X
Zhu
Xiongwei
X
Skidmore
S Chad
SC
Perry
George
G
Sayre
Lawrence M
LM
Smith
Mark A
MA
Lee
Hyoung-Gon
HG
D000447:Aldehydes / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D024161:Collagen Type XI / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009447:Neuroblastoma; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C403894:4-oxo-2-nonenal; D000447:Aldehydes; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D007770:L-Lactate Dehydrogenase; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4