Lipid peroxidation end product 4-hydroxy-trans-2-nonenal triggers unfolded protein response and heme oxygenase-1 expression in PC12 cells: Roles of ROS and MAPK pathways

doi:10.1016/j.tox.2013.11.007

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Title:	Lipid peroxidation end product 4-hydroxy-trans-2-nonenal triggers unfolded protein response and heme oxygenase-1 expression in PC12 cells: Roles of ROS and MAPK pathways
Authors:	Lin, Meng-Han Yen, Jui-Hung Weng, Ching-Yi Wang, Lisu Ha, Choi-Lan Wu, Ming-Jiuan
Contributors:	生物科技系食品科技系保健營養系
Keywords:	4-HNE Unfolded protein response ER stress HO-1 p38 MAPK
Date:	2014-01
Issue Date:	2015-05-06 21:22:29 (UTC+8)
Publisher:	Elsevier Ireland Ltd
Abstract:	This study investigates the roles of ROS overproduction and MAPK signaling pathways in the induction of unfolded protein response (UPR) and the expression of Phase II enzymes in response to 4-hydroxy-trans-2-nonenal (4-HNE) in a neuronal-like catecholaminergic PC12 cells. Our results showed that 4-HNE triggered three canonical pathways of UPR, namely IRE1-XBP1, PERK-eIF2 alpha-ATF4 and ATF6, and induced the expression of UPR-targeted genes, GRP78, CHOP, TRB3, PUMA, and GADD34, as well as Phase II enzymes, HO-1 and GCLC. 4-HNE also induced apoptosis, intracellular calcium accumulation, caspase-3 activation, and G(0)/G(1) cell cycle arrest, which was correlated with the increased expression of GADD45 alpha. The addition of tiron, a cellular permeable superoxide scavenger, scavenged 4-HNE-mediated ROS formation, but did not alleviate cytotoxicity, or the expression of UPR-targeted genes or Phase II enzymes, indicating that ROS overproduction per se did not play a major role in 4-HNE-caused deleterious effects. HO-1 expression was attenuated by Nrf2 siRNA and chemical chaperone 4-phenylbutyrate (4-PBA), suggesting HO-1 expression was regulated by Nrf2-ARE, which may work downstream of ER stress. 4-HNE treatment promptly induced ERK, JNK and p38 MAPK activation. Addition of p38 MAPK specific inhibitor SB203580 attenuated HO-1 upregulation, but enhanced expression of CHOP, PUMA and TRB3, and cytotoxicity. These results indicate that 4-HNE-induced transient p38 MAPK activation may serve as an upstream negative regulator of ER stress and confer adaptive cytoprotection against 4-HNE-mediated cell injury. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
Relation:	Toxicology, v.315, pp.24-37
Appears in Collections:	[Dept. of Food Science & Technology] Periodical Articles [Dept. of Health and Nutrition (including master's program)] Periodical Articles [Dept. of Biotechnology (including master's program)] Periodical Articles

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