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DNA Damage and Cellular Stress Responses

Reactive Oxygen Species Mediated Sustained Activation of Protein Kinase C and Extracellular Signal-Regulated Kinase for Migration of Human Hepatoma Cell Hepg2

¹ Department of Medical Technology and ² Graduate Institute of Medicine, Tzu Chi University; and Departments of ³ Ophthalmology and ⁴ Dermatology, Tzu Chi General Hospital, Hualien, Taiwan

Requests for reprints: Wu Wen-Sheng, Department of Medical Technology, Tzu Chi University, No. 701, Chung Yang Road, Section 3, Hualien 970, Taiwan. Phone: 3-8567285 ext 7512; Fax: 3-8571917. E-mail: wuws{at}mail.tcu.edu.tw

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) can trigger growth inhibition, epithelial-mesenchymal transition (EMT)–like cell scattering, and migration of hepatoma cells HepG2 in a protein kinase C- (PKC-)–dependent manner. Saikosaponin a, an ingredient of antitumorigenic Chinese herb Sho-Saiko-to, inhibited cell growth but did not induce EMT-like cell scattering and cell migration of HepG2. Saikosaponin a and TPA induced transient (for 30 minutes) and sustained (until 6 hours) phosphorylation of extracellular signal-regulated kinase (ERK), respectively. Generation of the reactive oxygen species (ROS) was induced by TPA, but not saikosaponin a, for 3 hours. As expected, scavengers of ROS, such as superoxide dismutase, catalase, and mannitol, and the thiol-containing antioxidant N-acetylcystein dramatically suppressed the TPA-triggered cell migration but not growth inhibition of HepG2. The generation of ROS induced by TPA was PKC, but not ERK, dependent. On the other hand, scavengers of ROS and N-acetylcystein also prevented PKC activation and ERK phosphorylation induced by TPA. On the transcriptional level, TPA can induce gene expression of integrins ₅, ₆, and ß₁ and reduce gene expression of E-cahedrin in a PKC- and ROS-dependent manner. In conclusion, ROS play a central role in mediating TPA-triggered sustained PKC and ERK signaling for regulation of gene expression of integrins and E-cahedrin that are responsible for EMT and migration of HepG2. (Mol Cancer Res 2006;4(10):747–58)

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