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CELLULAR AND MOLECULAR

Ginsenoside-Rh2-Induced Mitochondrial Depolarization and Apoptosis Are Associated with Reactive Oxygen Species- and Ca²⁺-Mediated c-Jun NH₂-Terminal Kinase 1 Activation in HeLa Cells

Cell Signal Transduction Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea (Y.-M.H.); and Division of Pharmaceutical Biosciences, College of Pharmacy, Research Institute of Pharmaceutical Sciences (J.-H.L., J.-S.C., B.-D.P., H.Y., S.-K.L.) and National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy (H.-K.N.), Seoul National University, Seoul, Korea

We show here that Ca²⁺ and reactive oxygen species (ROS) are involved in the up-regulation of c-Jun NH₂-terminal kinase 1 (JNK1) activity during apoptosis induced by ginsenoside Rh2 (G-Rh2) in HeLa, MCF10A-ras, and MCF7 cells. Addition of antioxidants such as N-acetyl-L-cysteine or catalase attenuates G-Rh2-induced ROS generation, JNK1 activation, and apoptosis. The overexpression of catalase down-regulates caspase-3 and JNK1 activities. G-Rh2 treatment of cells results in mitochondrial depolarization, second mitochondrial activator of caspase release, and translocation of Bax into the mitochondria, and these events are inhibited by antioxidants. Ca²⁺ is also involved in mitochondrial depolarization during G-Rh2-induced apoptosis. These results suggest that ROS and Ca²⁺ are important signaling intermediates leading to stress-activated protein kinase/extracellular signal-regulated kinase kinase 1/JNK1 activation and depolarization of the mitochondrial membrane potential in G-Rh2-induced apoptosis.

Address correspondence to: Dr. Seung-Ki Lee, Division of Pharmaceutical Biosciences, College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul, 151-742, Korea. E-mail: sklcrs{at}snu.ac.kr

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