Roles of SIRT1 and Phosphoinositide 3-OH Kinase/Protein Kinase C Pathways in Evodiamine-Induced Human Melanoma A375-S2 Cell Death

  • Wang Che
    China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University Department of Pharmacology, Shenyang Pharmaceutical University
  • Wang Min-wei
    Department of Pharmacology, Shenyang Pharmaceutical University
  • 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 University

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We previously demonstrated that evodimine isolated from Evodia rutaecarpa (Goshuyu in Japan) induced apoptosis in human malignant melanoma A375-S2 cells within 24 h. In this study, TUNEL assay also indicated that one cause of A375-S2 cell death induced by evodiamine was apoptosis. After treatment with evodiamine for the indicated time periods, anti-apoptotic protein SIRT1 expression was decreased; p53 expression and its phosphorylation were both enhanced, whereas transient induction of downstream p21 was not enough to promote cell cycle arrest. Inhibition of the phosphoinositide 3-OH kinase (PI3-K)/protein kinase C (PKC) survival pathway as well as subsequent inhibition of the ERK cascade might contribute to evodiamine-induced cell death. In addition, p53 activation in response to evodiamine administration was correlated with the activation of the PI3-K/PKC pro-apoptotic pathway, but did not require ERK participation. The inhibition of the PI3-K/PKC survival pathway might be responsible for SIRT1 inactivation and increased Bax/Bcl-2 expression ratio in evodiamine-induced cell death.<br>

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