Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/13286
標題: 鋅缺乏在鼠腦瘤細胞誘發細胞凋亡機制探討
Zinc Deficiency Induces Apoptotic Death in C6 Rat Glioma Cell
作者: 葉錦鴻
Yeh, Jiin-Horng
關鍵字: zinc deficiency;鋅缺乏;apoptosis;細胞凋亡
出版社: 獸醫學系暨研究所
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摘要: 
鋅離子在體內參與許多重要的功能如:轉錄因子活性、去氧核醣核酸的修復、細胞生長、細胞凋亡及細胞訊息傳遞等功能。越來越多的證據顯示當細胞鋅離子缺乏時會誘發細胞凋亡而造成細胞的損傷,但其相關的機制尚未明確。根據目前實驗的發現,鋅缺乏導致的細胞損傷與數種細胞訊息傳遞路徑如MAPK、PKC、PPAR、caspase等的活性變化有關。本實驗利用膜穿透性鋅離子螯合劑TPEN處理C6鼠神經膠瘤細胞,探討鋅缺乏對C6細胞的細胞損傷是否與這些常見的細胞訊息傳遞路徑有關。在乳酸去氫酶釋出試驗中可見TPEN處理造成細胞損傷呈現濃度及時間依賴性。加入等濃度的鋅離子可完全減少TPEN造成的細胞損傷。TPEN處理的細胞會出現去氧核醣核酸斷裂片段、 凋亡小體及凋亡細胞群,這些都顯示TPEN處理會造成細胞凋亡。在此TPEN造成的細胞凋亡中,可見caspase-3的活化合併利用廣效型caspase抑制劑, zVAD-fmk,可抑制TPEN造成的毒性,顯示TPEN造成的細胞凋亡與caspase-3路徑相關。鋅缺乏造成的細胞凋亡亦與細胞週期相關蛋白有關,在TPEN處理的細胞中可見p53蛋白的磷酸化、p21蛋白的累積、細胞週期素A及D蛋白的減少。藥理學上顯示添加anisomycin (MAPK活化劑)、PMA (PKC活化劑)、BADGE (PPAR抑制劑)於TPEN處理細胞中具有保護作用,此外anisomycin、PMA、BADGE添加於TPEN處理細胞中亦可明顯減少凋亡細胞及caspase-3的活性。有趣的是,在TPEN處理細胞中加入BADGE可增加ERK的磷酸化及PKC蛋白量,顯示BADGE參與MAPK及PKC訊息傳遞路徑。綜合以上實驗結果,TPEN可造成典型的細胞凋亡特徵其細胞訊息路徑與ERK及PKC路徑的活性下降有關,其中BADGE在TPEN處理細胞中可增加ERK的磷酸化及PKC蛋白量,減少TPEN對C6細胞造成的傷害。

Zinc plays a crucial role in the functions of transcription factors, DNA repair, cell growth, apoptosis and cell signaling. Increasing evidence shows that zinc depletion induces cell apoptosis in vulnerable cells, but the underlying mechanisms are as yet uncertain. According to recent experimental findings, zinc depletion-induced cell injury is associated with alterations in several cellular signaling molecules such as, MAPK, PKC, PPAR and caspases. To elicit the effect of zinc depletion on cell alterations and the possible cell signaling involvement, C6 rat glioma cells were treated with the membrane permeable zinc-selective chelator, TPEN. TPEN exposure induced C6 cell death in a concentration- and time-dependent manner based on LDH efflux analysis. TPEN-induced cell damage was completely reversed by the addition of equimolar zinc. TPEN-induced cell death was accompanied by the occurrence of oligonucleosomal DNA fragmentation, apoptotic bodies and subG1 cell population, indicating the involvement of apoptotic cell death. Caspase-dependent apoptosis in TPEN-treated cells was elicited by the activation of caspase-3 and suppression of toxicity by a broad-spectrum caspase inhibitor, zVAD-fmk. Zinc depletion induces cell apoptosis associated with cell cycle proteins. Within the TPEN-treated cells, the induction of p53 phosphorylation, accumulation of p21, decline of cyclin A and cyclin D were demonstrated. Pharmacological assay revealed the protective effects of anisomycin (a MAPK activator), phorbol 12-myristate 13- acetate (PMA; a PKC activator) and BADGE (a PPARγ antagonist) against TPEN-induced C6 cell death. Furthermore, the apoptotic cell death and caspase-3 activity were significantly suppressed by administration of anisomycin, PMA or BADGE in TPEN-treated C6 cell. Intriguingly, BADGE increased ERK phosphorylation and PKC protein in TPEN-treated C6 cell, indicating the involvement on MAPK and PKC signaling cascades. Taken together, these findings suggest TPEN induced typically apoptotic characteristics in C6 cells through downregulation of ERK and PKC signaling cascades and the protection effects of BADGE against TPEN-induced C6 cell death through upregulation of ERK phosphorylation and PKC protein.
URI: http://hdl.handle.net/11455/13286
其他識別: U0005-2508200608003800
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