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標題: 正-丁烯基苯藉由抑制二型S週期激酶相關蛋白誘導惡性腦瘤細胞老化
Cellur Senescence Mediated by Burylidenephthalide-Induced Downregulation of S-Phase Kinase-associated Protein 2
作者: 黃茂軒
Huang, Mao-Hsuan
關鍵字: 細胞分裂S期相關激酶多型性神經膠母細胞瘤
S-phase associated kinase protein 2
glioblastoma multiform
promoter assay
出版社: 生命科學系所
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摘要: 目前,醫藥市場上尚未有應用於人類惡性腦瘤治療之標靶藥物。正-丁烯基苯(n-butylidenephthalide, BP)是一個從當歸(Angelica sinenisis)萃取的純物質。在我們先前的研究中證實,正-丁烯基苯能夠讓人類多型性神經膠質細胞瘤生長延緩並增加細胞凋亡。除此之外,我們也發現隨著劑量提升,正-丁烯基苯能夠讓惡性腦瘤細胞老化(senescence)。細胞分裂S期相關激酶(S-phase kinase-associated protein 2, Skp2),一個細胞週期的調控者,被發現在許多人類腫瘤細胞中大量活化,當惡性腫瘤細胞中Skp2如果受到抑制,則會導至癌細胞老化並凋亡。為了證實BP的抑制腫瘤能力與Skp2有關,首先利用蛋白質免疫技術分析,結果顯示,正-丁烯基苯Α抑制Skp2的表現,進而造成cyclin-dependent kinase inhibitor的累積,最終誘導細胞走向衰老。若利用外來載體過量表現Skp2在人類惡性腦瘤細胞,則正-丁烯基苯誘導的老化的現象就顯著降低。此外藉由啟動子冷光報導載體及染色質免疫沉澱技術,我們發現BP是透過影響其轉錄因子Sp1鍵結至啟動子的能力,同時BP也會抑制Sp1的表現進而降低Skp2的轉錄活性。更進一步,在裸鼠皮下人類惡性腦瘤動物模式中,以正-丁烯基苯進行口服給藥治療,藉由免疫組織切片染色,我們觀察到與細胞實驗一致的結果。因此,經由細胞與動物實驗,本研究證實,正-丁烯基苯可能部份藉由抑制細胞分裂S期相關激誘導惡性腦瘤細胞老化,並達到治瘤惡性腦瘤的效果。
Developing an effective drug for treating human glioblastoma multiform (GBM) has been persistently investigated. A pure compound n-butylidenephthalide (BP), isolated from Angelica sinesis, has been shown the activities to arrest the growth and initiate apoptosis of GBM. In this study we further demonstrated that BP treatment accelerated the cell senescence in a dose-dependent manner in vitro and in vivo. In addition, S-phase kinase-associated protein 2 (Skp2), generally upregulated in cancer cells, was downregulated in BP-treated GBM cells. We also found that restoring the Skp2 protein level by exogenous overexpression prevented the BP-induced cell senescence, strengthening the linkage between cell senescence and Skp2 expression. Promoter binding analysis further detailed that the BP-mediated SP1 reduction may involved in the Skp2 downregulation. In summary, these results emphasize that BP-triggered apoptosis and senescence in GBM cells are highly associated with its control on Skp2 regulation.
其他識別: U0005-3101201314190700
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