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研究生:葉亭均
研究生(外文):Ting-Chun Yeh
論文名稱:探討Genistein在人類肝癌細胞的抗癌作用機轉
論文名稱(外文):Investigation of Anticancer Mechanism of Genistein inHuman Hepatocellular Carcinoma Hep3B Cells
指導教授:顧記華顧記華引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:94
語文別:中文
論文頁數:78
中文關鍵詞:genistein內質網迫力CHOP細胞凋亡類黃酮
外文關鍵詞:genisteinER stressCHOPapoptosisflavonoid
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在本篇論文中,我們針對一系列類黃酮化合物做抗癌機制方面的探
討。首先我們使用sulforhodamine B (SRB) assay 對類黃酮類化合物進行篩選,探討其針對肝癌細胞生長的抑制作用,結果顯示genistein、quercetin與epigallocatechin gallate (EGCG)對於抑制癌細胞生長均有不錯的效果,其IC50 分別為21.4、49.2 與82.2 µM。關於類黃酮化合物,以前雖然已經有很多研究,但這些化合物與另一條最近常被研究的細胞凋亡途徑,也就是「內質網壓力(ER stress)」的關係卻是很少被提到的,因此本研究的重點就是在探討這些化合物與內質網壓力的關係。我們檢視了內質網壓力相關的蛋白C/EBP homologous protein (CHOP),發現這些類黃酮當中,有些會引起細胞內轉錄因子CHOP 的表現增加,而且引起CHOP 增加的程度和其所造成的抑制細胞生長的程度呈現不錯的正相關(R=0.76)。由於genistein 是抑制細胞生長及引發CHOP 表現最顯著的化合物,因此,本論文選擇genistein 做詳細機轉的探討。藉由西方墨點法,我們發現除了引發CHOP的作用外,在genistein 作用下,其他跟內質網壓力相關的蛋白質也都發現有活化的現象,如:造成GRP78 的表現增加以及引起caspase-12 的活化。由於CHOP 的增加與genistein 所造成的細胞凋亡有不錯的正向關連,因此我們進一步探討CHOP 在genistein 所造成的細胞凋亡中,扮演著什麼樣的
角色。結果顯示,在使用antisense CHOP 抑制了CHOP 蛋白的情況下,genistein 所引起的作用也會被抑制掉,如細胞週期中的subG1 期以及caspase-3 的活化現象都有被抑制的現象。此外,我們也發現genistein 會造成細胞內產生大量Reactive oxygen species (ROS)。然而,藉由一些抗氧化劑(trolox 與N-acetyl-L-cysteine (NAC))的處理與探討,我們的結果認為這些ROS 對於細胞週期及CHOP 的表現是沒有影響的。另一方面,我們對粒線體膜電位進行測量,發現genistein 在短時間即會造成粒線體膜電位喪失,
且使用cyclosporine A 抑制了粒線體膜電位的喪失,可以減緩部分細胞凋亡的情形。以上結果顯示,除內質網之外,粒線體也在genistein 造成的細胞凋亡扮演著一些角色,且兩者之間可能彼此交互作用來造成肝癌細胞的凋亡。
We have performed anti-tumor screening of a lot of flavonoids in human hepatocellular carcinoma Hep3B cells by sulforhodamine B (SRB) assays. We found that several flavonoids, including genistein, quercetin and epigallocatechin gallate (EGCG), displayed effective anti-tumor effect with IC50 of 21.4、49.2 and 82.2 µM, respectively. Although numerous mechanisms about flavonoids have been suggested, little is known about the involvement of endoplasmic reticulum (ER) stress, another pathway that induces cell apoptosis. In this study, we focused our research on ER stress-related investigation. Accordingly, the detection of ER stress-relevant marker proteins was carried out in cells responsive to the effective flavonoids. At first, the transcription factor C/EBP homologous protein (CHOP) was examined and the data demonstrated that genistein, a soy-derived isoflavone, was the most effective flavonoid to induce a dramatic increase of CHOP expression. Furthermore, genistein induced the up-regulation of GRP78, a marker of ER stress, and the cleavage of caspase-12, an ER stress-relevant caspase. It has been well evident that CHOP plays a role in the inhibition of cell growth and the induction of apoptosis. To clarify the functional role of CHOP, cells were transiently transfected with morpholino CHOP antisense oligonucleotides. The data showed that the subG1 phase in the cell cycle and caspase-3 activation induced by genistein were partly diminished in CHOP-deficient cells. Besides, we also found that genistein could induce the production of ROS. However, under the treatment of antioxidant trolox and NAC, the genistein-induced cell cycle progression and the increase of subG1 phase were not modified, suggesting thatthe ROS production did not contribute to genistein-induced effect. Furthermore, the data showed that genistein was able to induce the loss of mitochondria membrane potential. The pharmacological inhibitor, cyclosporine A, could significantly attenuate the loss of mitochondrial membrane potential and could partly diminish genistein-induced effect, suggesting that an interaction with mitochondria might involve in genistein-induced apoptosis. Taken together, it is suggested that genistein is an effective flavonoid that induces apoptotic cell death through, at least partly, the CHOP-involved ER stress. The mitochondria-mediated pathways may also contribute to genistein-induced apoptosis in Hep3B cells.
縮寫表•••••••••••••••••••••••• Ⅰ
中文摘要••••••••••••••••••••••• Ⅲ
英文摘要••••••••••••••••••••••• Ⅴ
背景••••••••••••••••••••••••• 1
實驗材料與方法•••••••••••••••••••• 13
1.細胞培養••••••••••••••••••••• 14
2.細胞計數••••••••••••••••••••• 14
3.SRB assay•••••••••••••••••••• 14
4.TUNEL assay••••••••••••••••••• 15
5.免疫螢光染色法•••••••••••••••••• 15
6.流式細胞儀•••••••••••••••••••• 16
7.蛋白質萃取與定量••••••••••••••••• 17
8.西方墨點法•••••••••••••••••••• 18
9.Transfection••••••••••••••••••• 20
10.Comet assay••••••••••••••••••• 21
11.資料分析與統計••••••••••••••••• 21
實驗結果••••••••••••••••••••••• 23
實驗討論••••••••••••••••••••••• 31
結論••••••••••••••••••••••••• 43
圖表••••••••••••••••••••••••• 44
參考文獻••••••••••••••••••••••• 70
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1. 16. 吳安妮,平衡計分卡之精髓、範疇及整合 (上),會計研究月刊,民國92年7月,第211期,頁45-54。
2. 14. 吳安妮,平衡計分卡重點發展方向—與智慧資本相結合、強化策略核心組織,會計研究月刊,民國93年7月,第224期,第98-108頁。
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