THE ESSENTIAL ROLE OF ERK IN 4-OXO-2-NONENAL MEDIATED CYTOTOXICITY IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS.
J Neurochem. 2009 Jan 13;
Authors: Lee HP, Zhu X, Zhu X, Perry G, Sayre LM, Smith MA, Lee HG
Abstract Previous studies suggest that lipid peroxidation byproducts, such as 4-hydroxynonenal (HNE) and 4-oxo-2-nonenal (ONE), induces 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 (MAPK) 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 no change in 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-mediated cytotoxicity mechanism and that of HNE. 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 for ONE-mediated cytotoxicity and that ERK is an upstream component of p53-mediated apoptosis.
PMID: 19183271 [PubMed - as supplied by publisher]