Role of ERK in hydrogen peroxide-induced cell death of human glioma cells.
Oxidative stress is known to induce cell death in a wide variety of cell types, apparently by modulating intracellular signaling pathways. Activation of extracellular signal-regulated kinase (ERK) in oxidative stress remains controversial. In some cellular systems, the ERK activation is associated with protection against oxidative stress, while in other system, the ERK activation is involved in apoptotic cell death. The present study was undertaken to examine the role of ERK activation in H2O2-induced cell death of human glioma (A172) cells. H2O2 resulted in a time- and dose-dependent cell death, which was largely attributed to apoptosis. H2O2 treatment caused marked sustained activation of ERK. The ERK activation and cell death induced by H2O2 was prevented by catalase, the hydrogen peroxide scavenger, and U0126, an inhibitor of ERK upstream kinase MEK1/2. Transient transfection with constitutive active MEK1, an upstream activator of ERK1/2, increased H2O2-induced cell death, whereas transfection with dominant-negative mutants of MEK1 decreased the cell death. The ERK activation and cell death caused by H2O2 was inhibited by antioxidants (N-acetylcysteine and trolox), Ras inhibitor, and suramin. H2O2 produced depolarization of mitochondrial membrane potential and its effect was prevented by catalase and U0126. Taken together, these findings suggest that growth factor receptor/Ras/MEK/ERK signaling pathway plays an active role in mediating H2O2-induced apoptosis of human glioma cells and functions upstream of mitochondria-dependent pathway to initiate the apoptotic signal.
Lee
Won Chang
WC
Department of Neurosurgery, College of Medicine, Pusan National University, Pusan 602-739, Korea.
Choi
Chang Hwa
CH
Cha
Seung Heon
SH
Oh
Hyun Lim
HL
Kim-
Yong Keun
YK
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D015151:Immunoblotting; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D017978:Receptors, Growth Factor / Q000378:metabolism; D014162:Transfection
D017978:Receptors, Growth Factor; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases