Silibinin Activated p53 and Induced Autophagic Death in Human Fibrosarcoma HT1080 Cells via Reactive Oxygen Species-p38 and c-Jun N-Terminal Kinase Pathways
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概要
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Our previous research demonstrated that hepatic-protectant silibinin induced autophagy in human fibro-sarcoma HT1080 cells through reactive oxygen species (ROS) pathway. Pifithrin-α (PFT-α), a specific inhibitor of p53, reduced autophagy and reversed silibinins growth-inhibitory effect; besides, PFT-α decreased the activation of caspase-3, a crucial executor of apoptosis. Silibinin upregulated expression of p53/phosphorylated-p53 (p-p53) in a time-dependent manner. Catalase (scavenger of H2O2), superoxide dismutase (SOD) (scavenger of O2•−), and SB203580 (inhibitor of p38) attenuated upregulation of p53 expression, suggesting that p53 might be partially regulated by ROS-p38 pathway. On the other hand, c-Jun N-terminal kinase (JNK) increased autophagic death in silibinin-treated cells, and JNK/p-JNK expression was upregulated by silibinin time-dependently. Inhibition of JNK by SP600125 did not influence generation of ROS. Scavengers of H2O2 or O2•− showed no effect on expression of JNK/p-JNK, indicating that JNK might not correlate with ROS in this process. However, activation of p53 was suppressed by SP600125; therefore the function of p53 was possibly controlled by JNK as well. Western blotting analysis showed that PFT-α reduced activation of extracellular regulated kinase1/2 (ERK1/2) and expression of protein kinase B (PKB, or Akt)/p-Akt. PD98059 (inhibitor of mitogen-activated protein kinase kinase (MEK)/ERK) and wortmannin (inhibitor of phosphoinositide 3-kinase (PI3K)/Akt) enhanced silibinins cytotoxicity. Wortmannin augmented silibinin-induced autophagy, while PD98059 did not affect autophagic ratio. These results suggest that silibinin might induce p53-mediated autophagic cell death by activating ROS-p38 and JNK pathways, as well as inhibiting MEK/ERK and PI3K/Akt pathways.
著者
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TASHIRO Shin-ichi
Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University
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ONODERA Satoshi
Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University
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IKEJIMA Takashi
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical Unive
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Ikejima Takashi
China-japan Res. Inst. Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical Univ. Chn
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Duan Wen-Jun
China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical Unive
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Li Qi-Sheng
China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical Unive
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Xia Ming-Yu
China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical Unive
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Onodera Satoshi
Department Of Cinical And Biomedical Sciences Showa Pharmaceutical University
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Tashiro Shin-ichi
Department Of Cinical And Biomedical Sciences Showa Pharmaceutical University
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Xia Mingyu
China-japan Research Institute Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical Univer
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Ikejima Takashi
China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University
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Xia Ming-Yu
China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University
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Duan Wen-Jun
China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University
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Li Qi-Sheng
China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University
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