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Involvement of Intracellular Ca2+-and PI3K-Dependent ERK Activation in TCDD-Induced Inhibition of Cell Proliferation in SK-N-SH Human Neuronal Cells

Yang, Seun-Ah    (Institute for Drug Research, Yeungnam University   ); Lee, Yong-Soo    (College of Pharmacy, Duksung Women's University   ); Jin, Da-Qing    (College of Pharmacy, Yeungnam University   ); Jung, Jae-Wook    (College of Pharmacy, Yeungnam University   ); Park, Byung-Chul    (College of Pharmacy, Yeungnam University   ); Lee, Yoon-Seok    (College of Pharmacy, Yeungnam University   ); Paek, Seung-Hwan    (College of Pharmacy, Yeungnam University   ); Jeong, Tae-Cheon    (College of Pharmacy, Yeungnam University   ); Choi, Han-Gon    (College of Pharmacy, Yeungnam University   ); Yong, Chul-Soon    (College of Pharmacy, Yeungnam University   ); Yoo, Bong-Kyu    (College of Pharmacy, Yeungnam University   ); Kim, Jung-Ae    (College of Pharmacy, Yeungnam University ;  );
  • 초록

    2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) has previously shown to induce neurotoxicity through intracellular $Ca^{2+}$ increase in rat neurons. In this study we investigated the role and signaling pathway of intracellular $Ca^{2+}$ in TCDD-induced inhibition of neuronal cell proliferation in SK-N-SH human neuronal cells. We found that TCDD(10nM) rapidly increased the level of intracellular $Ca^{2+}$ , which was completely blocked by the extracellular $Ca^{2+}$ chelation with EGTA (1 mM) or by pretreatment of the cells with the non-selective cation channel blocker. flufenamic acid (200 ${\mu}M$ ). However, pretreatment of the cells with dantrolene (25 ${\mu}M$ ) and TMB-8(10 ${\mu}M$ ), intracellular $Ca^{2+}$ -release blockers, or a voltage-sensitive $Ca^{2+}$ channel blocker, varapamil (100 ${\mu}M$ ), failed to block the TCDD-induced $Ca^{2+}$ increase in the cells. In addition, TCDD induced a rapid and transient activation of phatidvlinositol 3-kinase (PI3K) and extracellular signal-regulated kinase 1/2(ERK1/2), which was ingnificantly blocked by the pretreatment with BAPTA, an intracellular $Ca^{2+}$ chelator, and LY294002, a PI3K inhibitor. Furthermore, inhibitors of PI3K, ERK, or an intracellular $Ca^{2+}$ chelator further potentiated the anti-proliferative effect of TCDD in the cells. Collectively, the results suggest that intracellular $Ca^{2+}$ and PI3K-dependent activation of ERK 1/2 may be involved in the TCDD-induced inhibition of cell proliferation in SK-N-SH human neuronal cells.

  • 주제어

    TCDD .   neurotoxicity .   ERK .   PI3K .   proliferation .   SK-N-SH human neuronal cells.  

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