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。

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.

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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