Inactivation of Ras and Changes of Mitochondrial Membrane Potential Contribute to Oridonin-Induced Autophagy in A431 Cells

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概要

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• We have previously shown that oridonin isolated from Rabdosia rubescens augmented apoptosis while inhibiting autophagy within 24 h in HeLa cells. However, the mechanisms between apoptosis and autophagy induced by oridonin in A431 cells are largely unknown. Here, it was found that autophagic level is significantly upregulated when A431 cells are pretreated with manumycin A (Ras specific inhibitor) compared with oridonin alone treatment, whereas cells precultured with GW5074 (Raf inhibitor) or PD98059 (ERK inhibitor) did not exhibit such an effect. Ras, but not Raf or ERK, was engaged in the control of oridonin-induced autophagy. At the same time, manumycin A contributes to oridonin-induced downregulation of Ras protein expression. Treatment with the combination of oridonin and manumycin A downregulated phosphorylation of Akt, downstream of phosphatidylinositol 3-OH kinase (PI3-K). Preincubation with the PI3-K inhibitor wortmannin and Akt inhibitor KP372-1 enhanced oridonin-induced apoptosis, whereas it inhibited oridonin-induced autophagy. However, under oridonin treatment, the expression of Beclin-1, which has autophagy-inducing activity, was reduced, suggesting that Beclin-1 did not participate in the oridonin-induced autophagy. Morphologic observations, DNA fragmentation analysis, and LDH activity-based assay showed that 3-methyladenine (3-MA), an inhibitor of autophagy, increased the apoptotic sensitivity of A431 cells to oridonin. In addition, manumycin A contributed to oridonin-induced decrease of mitochondrial membrane potential (Δψm), consistent with the upregulation of Bax/Bcl-2 ratio. In conclusion, Ras negatively regulated autophagy in oridonin-treated A431 cells, which might be associated with activation of class I PI3-K. Downregulation of Δψm and increasing of the ratio of Bax/Bcl-2 might also be partially responsible for the initiation of the autophagic process.

• 社団法人 日本薬理学会の論文
• 2007-09-20

著者

• Tashiro Shin-ichi

  Dep. Of Clinical And Biomedical Sciences Showa Pharmaceutical Univ. Jpn

• TASHIRO Shin-ichi

  Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University

• ONODERA Satoshi

  Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University

• IKEJIMA Takashi

  China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical Unive

• Wu Li-jun

  Department Of Phytochemistry Shenyang Pharmaceutical University

• Wu L

  Department Of Phytochemistry Shenyang Pharmaceutical University

• Onodera S

  Dep. Of Clinical And Biomedical Sciences Showa Pharmaceutical Univ. Jpn

• Onodera Satoshi

  昭和薬科大学 病態科

• Ikejima Takashi

  China-japan Res. Inst. Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical Univ. Chn

• CUI Qiao

  China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical Universit

• LI Dan

  China-Japan Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University

• CHEN Shen-geng

  China-Japan Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University

• Tashiro Shin-ichi

  Department Of Clinical And Biomedical Sciences Showa Pharmaceutical University

• Onodera Satoshi

  Department Of Cinical And Biomedical Sciences Showa Pharmaceutical University

• Tashiro Shin-ichi

  Department Of Cinical And Biomedical Sciences Showa Pharmaceutical University

• Li Dan

  China-japan Research Institute Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical Univer

• Cui Qiao

  China-japan Institute Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical University

• Tashiro S

  Department Of Clinical And Biomedical Sciences Showa Pharmaceutical University

• Onodera S

  Department Of Clinical And Biomedical Sciences Showa Pharmaceutical University

• Chen Shen-geng

  China-japan Institute Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical University

• Ikejima Takashi

  China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University

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