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題 名 | The Involvement of PI3-K/Akt-Dependent UP-Regulation of Mcl-1 in the Prevention of Apoptosis of Hep3B Cells by Interleukin-6=介蛋白六藉由調控Mc-1基因表現抑制肝癌細胞的細胞凋亡 |
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作 者 | 郭明良; 莊雙恩; 林明燦; 楊心元; | 書刊名 | 中華民國癌症醫學會雜誌 |
卷 期 | 17:2 2001.06[民90.06] |
頁 次 | 頁1-16 |
分類號 | 415.138 |
關鍵詞 | 介蛋白六; Mc-1基因; 肝癌細胞; 細胞凋亡; IL-6; |
語 文 | 英文(English) |
中文摘要 | 在很多種細胞中介白質六(IL-6)不單可以調節細胞的生長和分化還可引發肝癌細胞急性發炎反應蛋白的產生。我們最近的研究證實PI3-k/Akt和STAT3路徑皆可被IL-6的抗細胞凋亡效用調控而活化。研究指出在肝癌細胞Hep3B中,IL-6可保護細胞免於多種不同化學試劑,如:TGF-β、UV和視網酸所造成的細胞凋亡,證明IL-6對肝癌細胞的存活十分的重要。Mcl-1為Bcl-2家庭成員之一,在處理IL-6,4hr後Mcl-1可被快速地調升至四倍的表現量。短暫轉殖含有Mcl-1 (AS)的載體至Hep3B中,可降低約50-60% UK-6 的抗細胞凋亡的效果。這結果顯示IL-6為影響Mcl-1下游基因表現的調控者。因此,我們更進一步探究哪一個訊息傳導途徑為影響IL-6調升Mcl-1表現的途徑。在Hep3B細胞中,JAK/STAT3、ERK和PI3-k/Akt皆受IL-6刺激而活化。用一個不含有STAT3基因的突變株或JAK的抑制劑,如:AG490 來抑制JAK/STAT3活化後發現其並不影響 IL-6 調升 Mcl-1的表現;相同的,以 PD98059 處理也無法抑制住Mcl-1的表現。然而,在PI3-k抑制劑LY294002和wortmannin存在時IL-6所引發Mcl-1大量表現的現象會被減弱。在不表現Akt的細胞株中可以抑制IL-6引發的Mcl-1表現。綜合以上所得,我們的結果指出IL-6的抗細胞凋亡活性是經由PI3-k/Akt路徑來調控Mcl-1的表現。 |
英文摘要 | Interleukin-6 (IL-6) is a pleitrophic cytokine that not only regulates growth and differentiation of many cell types, but also induces production of acute phase proteins (AAP) in hepatocytes. Our previous works have demonstrated that both PI 3-K/Akt and STAT3 pathways were concomitantly activated and cooperatively mediated the anti-apoptotic effect of IL-6. This investigation reports that IL-6 protected cells against apoptosis induced by a variety of agents including, TGF-β, UV and retinoic acid (RA) in Hep3B cells, suggesting that IL-6 is a fundamental determinant of hepatic cell survival. Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated by IL-6, with a peak (approximately 3-4 fold) appearing at 4 h. Transient transfection of cells with a mcl-1 antisense vector, resulting in a 50-60% reduction of the anti-apoptotic effect of IL-6, indicating that Mcl-1 is a downstream effect of IL-6. Which signaling pathway transduced by IL-6 responsible for the Mcl-1 up-regulation was further investigated. In Hep3B cells, the JAK/STAT3, ERK, and PI 3-K/Akt pathways were activated by IL-6 stimulation. Blocking JAK/STAT3 activation with a dominant-negative mutant STAT3F or a JAK inhibitor AG490 could not influence IL-6-mediated Mcl-1 up-regulation. Similarly, PD98059 treatment, a MEK specific inhibitor, also failed to inhibit Mcl-1 expression. However, the IL-6- |
本系統中英文摘要資訊取自各篇刊載內容。