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博碩士論文 etd-0715108-145938 詳細資訊
Title page for etd-0715108-145938
論文名稱
Title
Goniothalamin 誘導肝癌細胞株經由TP53-dependent 與-independent 途徑之細胞凋亡
Goniothalamin induces TP53-dependent and -independent apoptosis in hepatocellular carcinoma derived cells
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
59
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2008-06-25
繳交日期
Date of Submission
2008-07-15
關鍵字
Keywords
肝癌細胞、細胞凋亡
HCC, apoptosis, Goniothalamin, Hep-3B, SK-Hep1, TP53
統計
Statistics
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中文摘要
本實驗的主旨在於探討goniothalamin (GTN) 於肝癌細胞株中引發細胞凋亡之分子機制。自Goniothalamus amuyo(恆春哥納香) 純化之GTN被發現對於人類肝癌SK-Hep1和Hep-3B具有毒殺之效果。藉由於570 nm吸收光譜的MTT試驗得知GTN在72小時的IC50在SK-Hep1和Hep-3B分別為7.5, 17 mM,且可引發肝癌細胞內氧化壓力的累積與細胞的死亡,而GTN與氧化物抑制劑N-actylcysteine同時處理則可回復細胞的存活率,並藉由γ-H2AX foci 的形成推測GTN可導致DNA的雙股斷裂。在SK-Hep1細胞中GTN藉由調控CCND, CCNE1, RB1和E2F1蛋白質使細胞停留於細胞週期之G0/G1時期,而在Hep-3B細胞中則是調控CCNB1使細胞停留於G2/M時期。GTN在SK-Hep1所引發的細胞凋亡與磷脂醯絲氨酸外翻且包含了外來與內在之途徑,但是於Hep-3B中只有外來之途徑,在SK-Hep1細胞株中GTN 藉由引發和TP53調控之機制導致細胞凋亡與細胞週期中止,反之而在TP53/FAS突變之Hep-3B中則無 。更重要的是GTN可誘發無論是TP53正常或TP53/FAS 之肝癌細胞的細胞凋亡,此外GTN可引發SK-Hep1細胞中TP53調控p21WAF1/Cip1 表現與Hep-3B中p21WAF1/Cip1與p27Kip1的表現量上升。這些結果顯示GTN可藉由不同的分子機制導致肝癌細胞的細胞凋亡。
Abstract
The objective was to study apoptotic effects and underlying molecular mechanisms of goniothalamin (GTN) in hepatocellular carcinoma (HCC)-derived cells. The GTN that isolated from Goniothalamus amuyon, was found to possess profound cytotoxic activities against human SK-Hep1 and Hep-3B cells in vitro. The cytotoxicity of GTN/cell viability was measured by MTT assay at 570-nm absorbance and the IC50 at 72 h were determined as 7.5, 17 mM in SK-Hep1 and Hep-3B respectively. The GTN induced cell death and accumulation of reactive oxygen species in HCC-derived cells. One reactive oxygen species inhibitor, N-actylcysteine, further restored cell viabilities post-GTN treatments. Formation of γ-H2AX foci suggested that GTN-induced DNA damages were double-strand breaks. The GTN arrested cell cycle at G0/G1 by regulation of CCND, CCNE1, RB1 and E2F1 proteins in SK-Hep1, and at G2/M by regulation of CCNB1 in Hep-3B cells. The GTN-induced apoptosis in HCC-derived cells were evidenced by phosphatidylserine externalization and involved both extrinsic and intrinsic pathways in SK-Hep1 cells, but only extrinsic pathway in Hep-3B cells. In SK-Hep1 cells, GTN induced apoptosis and cell cycle arrest through TP53-mediated pathway in contrast to that of TP53/FAS mutated Hep-3B cells. Importantly, GTN was able to induce apoptosis in both TP53 wild type and TP53/FAS mutated HCC-derived cells. On the other hand, GTN was able to induce TP53 and p21WAF1/Cip1 up-regulation in SK-Hep1 and Hep-3B cells and p27Kip1 up-regulation in Hep-3B cells. These results demonstrated that GTN induced apoptosis in HCC cells through distinct signaling pathways.
目次 Table of Contents
Abstract
Chinese………………………………………………………... 2
English ...……………………………...………………….…… 3
Introduction…………………………………………..……………. 4
Materials and Methods…………………………………………… 15
Results………………………………………………..……..……... 23
Figures………………………………………..……………..... 31
Discussion...…………………………………………………...…... 47
References…………………………………………………………. 51
Appendix……………………………………………………..……. 57
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