title: The essential role of ERK in 4-oxo-2-nonenal-mediated cytotoxicity in SH-SY5Y human neuroblastoma cells.
abstract: 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.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Hyun-Pil
authors.initials: HP
authors.lastname: Lee
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhu
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: S Chad
authors.initials: SC
authors.lastname: Skidmore
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Sayre
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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