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研究生:黃銘宏
研究生(外文):Ming-Hung Huang
論文名稱:石榴萃取之多酚(TMU023)造成人類神經膠質瘤細胞之死亡機制
論文名稱(外文):A polyphenol extract (TMU023) from pomegranate induces cell death in human glioma cells
指導教授:李宏謨李宏謨引用關係
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學檢驗生物技術學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:58
中文關鍵詞:神經膠質瘤細胞凋亡細胞自噬
外文關鍵詞:gliomaapoptosisAMPKautophagy
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石榴(pomegranate)學名為Punica granatum是石榴樹的果實。目前已知石榴可以造成細胞凋亡來抑制許多惡性癌細胞的生長,本論文利用從石榴萃取出的多酚物(polyphenol)— TMU023,來探討TMU023是否會造成U87MG神經膠質瘤細胞的生長抑制和細胞凋亡。實驗結果發現,TMU023會抑制U87MG神經膠質瘤細胞的生長,使細胞的cyclin E表現增加,抑制cyclin A和cyclin B的表現,因而使細胞週期停留在S期。我們也發現TMU023會改變細胞中Bax和Bcl-2的比例,使的細胞色素c(cytochrome c)離開粒線體,活化caspase-9造成PARP的斷裂而使細胞走向細胞凋亡。將U87MG神經膠質瘤細胞以TMU023處理之後,會活化AMPK(AMP activated protein kinase)造成細胞自噬的細胞死亡,我們利用chloroquine來抑制細胞自噬,結果發現chloroquine可以保護U87MG神經膠質瘤細胞,避免因TMU023造成的細胞死亡。TMU023、AICAR(5-aminoimidazole-4-carboxamide riboside)和metformin都能活化AMPK,增加autophagosome的形成使LC3被切割。我們結果證實TMU023會造成細胞的死亡是透過細胞凋亡和細胞自噬的途徑。
The extract of Pomegranate, fruit derived from the tree Punica granatum, has been shown to inhibit cell growth followed by apoptosis in many highly aggressive caner cells. In the present study, we demonstrated that treatment of human glioma U87MG cells with TMU023, a polyphenol isolated from Punica granatum, resulted in inhibition of cell growth [as evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide assay], arrest of cells in S phase of the cell cycle (as assessed by DNA cell cycle analysis), and induction of apoptosis (as evaluated by DNA ladder formation and flow cytometry). These events were associated an increase protein levels of cyclin E, down regulation of cyclin B and cyclin A and an alteration of the Bax:Bcl-2 ratio in favor of apoptosis. Indeed, TMU023 induced cleavage of poly(ADP-ribose) polymerase, release of cytochrome c from mitochondria, and activation of caspase-9 in U87MG cells. Incubation of U87MG cells with TMU023 activated the AMP activated protein kinase (AMPK), which may lead to autophagic cell death. Inhibition of autophagy by treatment with chloroquine (10 μM) protected U87MG cells from TMU023-induced cell death. Both TMU023, AICAR and metformin, another AMPK stimulator, increased autophagosome formation and LC-3 II cleavage (as demonstrated by immunoblotting). Our results suggest that in addition to promoting death via apoptotic pathway, pomegranate may induce autophagic cell death.
目錄
中文摘要 I
Abstract III
目錄 V
圖目錄 VII
縮寫表 IX
第一章 緒論 1
一、腦瘤(brain tumor) 1
二、AMP-activated protein kinase(AMPK) 2
三、細胞週期(cell cycle) 4
四、細胞凋亡(apoptosis) 5
五、細胞自噬(autophagy) 7
六、石榴(Pomegranate) 9
七、Chloroquine 10
第二章 實驗材料及方法 12
一、藥品試劑 12
二、常用溶液 14
三、常用儀器 16
四、U87MG神經膠質瘤細胞株(U87MG glioma cell line)繼代培養 17
五、細胞毒性之試驗(MTT assay) 18
六、細胞蛋白質的測定 18
七、細胞週期的測定(propidium iodide染色法) 20
八、統計分析 20
第三章 實驗結果 21
一、TMU023降低U87MG神經膠質瘤細胞的存活率 21
二、TMU023抑制U87MG神經膠質瘤細胞的細胞週期 21
三、TMU023造成U87MG神經膠質瘤細胞的細胞凋亡 22
四、TMU023誘導U87MG神經膠質瘤細胞AMPK的活化和p27的Thr198磷酸化 23
五、TMU023刺激U87MG神經膠質瘤細胞的細胞自噬 23
六、Chloroquine對U87MG神經膠質瘤細胞中細胞自噬的影響 24
第四章 討論 25
第五章 參考文獻 29

圖目錄
Figure 1. Anti-proliferative effects of TMU023 in U87MG cells. 39

Figure 2. Effects of TMU023 treatment of U87MG cells on protein expression of cyclin E. 40

Figure 3. Effects of TMU023 treatment of U87MG cells on protein expression of cyclin A. 41

Figure 4. Effects of TMU023 treatment of U87MG cells on protein expression of cyclin B. 42

Figure 5. Effects of TMU023 treatment of U87MG cells on protein expression of Cdk2. 43

Figure 6. Effects of TMU023 treatment of U87MG cells on protein expression of p21. 44

Figure 7. Effects of TMU023 treatment of U87MG cells on protein expression of p27. 45

Figure 8. Effects of TMU023 on cell cycle distribution in U87MG cells. 46

Figure 9. Effects of U87MG on the PARP cleavage caused by treatment with TMU023. 47

Figure 10. The time-dependent effects of TMU023 on PARP cleavage in U87MG glioma cells. 48

Figure 11. Effects of TMU023 treatment of U87MG cells on protein expression of Bcl-2. 49

Figure 12. Effects of TMU023 treatment of U87MG cells on protein expression of Bax. 50

Figure 13. Effects of U87MG on the caspase-9 cleavage caused by treatment with TMU023. 51

Figure 14. Inhibition of caspase activation reverse TMU023 induced apoptosis. 52

Figure 15. Effects of TMU023 on AMPK phosphorylation in U87MG cells. 53

Figure 16. Effects of TMU023 on p27 phosphorylation in U87MG cells. 54

Figure 17. TMU023 increased the accumulation of microtubule -associated protein 1 light chain 3 II (LC3-II) in U87MG cells. 55

Figure 18. Chloroquine induced cell death in U87MG cells. 56

Figure 19. Chloroquine inhibits TMU023-induced cell death in U87MG cells. 57

Figure 20. Effects of chloroquine on TMU023 increased the accumulation of microtubule -associated protein 1 light chain 3 II (LC3-II) in U87MG cells. 58
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