近年來，細胞老化被認為是一種腫瘤抑制機制，外來壓力、致癌基因、端粒的穩定度與藥物處理皆可能造成細胞老化。細胞老化能抵抗細胞在不同壓力刺激下所產生的癌化現象，並有效抑制腫瘤的生長與促進癌症治療效果，因此被認為是一個新穎的抗癌策略。現今已有利用細胞老化作為抗癌機制的合成化合物出現，而天然物也相繼被報導能透過細胞老化抑制癌細胞生長，並且具有低毒性與低副作用的優勢。本研究使用的紫檀芪是白藜蘆醇的類似物，在2014年被報導是個有潛力的端粒酶活性抑制劑。端粒酶在癌細胞中有大量表現的情形，但在正常細胞表現量極低，因此可做為抗癌藥物的標靶。此外，抑制端粒酶能造成細胞老化的現象。過去許多研究指出p53在細胞老化中扮演著著重要的角色，並且p53也被報導是端粒酶轉錄的負調控因子。本研究利用兩株不同p53表現的人類非小細胞肺癌細胞株H460 (p53 wide type)與H1299 (p53 null)探討紫檀芪是否會藉由抑制端粒酶活性與蛋白表現誘導老化現象進而抑制肺癌細胞生長，並進一步加入H1299轉殖p53基因 (H1299-p53+)的細胞株探討端粒酶抑制後造成的細胞老化機轉與p53的關係。在細胞實驗中，利用Trypan blue 試驗評估紫檀芪對H460與H1299細胞生長的影響，配合流式細胞儀分析細胞週期分布，以聚落形成試驗 (colony formation assay)評估細胞生長停滯現象，利用顯微鏡與共軛焦顯微鏡觀察三株肺癌細胞 (H460、H1299、H1299-p53+)處理紫檀芪後的形態變化、老化指標 (senescence associated β–galactosidase, SA-β-gal)活性與異染色質點 (senescence associated heterochromatin foci, SAHF)的形成。接著以彗星試驗 (comet assay)分析DNA斷裂現象與利用 Real-Time PCR分析紫檀芪對端粒酶活性的抑制效果。以西方墨點法分析細胞週期調控蛋白、端粒酶與DNA損傷機制相關蛋白的表現，接著轉殖端粒酶質體進入H460肺癌細胞中使其端粒酶過度表現，評估端粒酶過度表現之H460肺癌細胞處理紫檀芪後，老化現象是否回復。實驗結果顯示紫檀芪能降低H460與H1299細胞株的細胞存活率與生長速率，且隨著處理時間延長則產生死亡，其中H1299細胞株對紫檀芪的敏感度較低。在細胞週期分析方面，經紫檀芪處理後H460與H1299細胞株皆表現S phase停滯現象以及S期細胞素cyclin E、cyclin A、p53、p21與p27表現量上升，cdc25A表現量下降。聚落形成試驗顯示細胞生長不可回復的情形。細胞的型態也變肥大扁平且具有老化SA-β-gal活性以及老化相關異染色質點的形成，尤其以H460細胞株較明顯。H1299-p53+細胞株也發現細胞老化現象較p53缺乏型的H1299細胞株明顯，這顯示具正常功能的p53細胞容易被紫檀芪誘發老化現象。此外，我們也在實驗中觀察到DNA斷裂現象與DNA損傷機制的參與。在端粒酶活性分析中 H460、H1299與H1299-p53+細胞株的端粒酶活性皆受到抑制，但端粒酶蛋白表現則只有H460與H1299-p53+被明顯抑制，這表示p53可能會負調控端粒酶的轉錄使其蛋白表現量下降，因此加強紫檀芪對端粒酶的抑制效果與誘導的老化現象。最後，在端粒酶過度表現實驗中，發現使H460肺癌細胞株端粒酶過度表現能夠減少紫檀芪處理導致的細胞DNA損傷現象並減少老化SA-beta-gal的活性。綜合以上實驗結果，證實紫檀芪能透過抑制端粒酶活性與蛋白表現進而誘發人類非小細胞肺癌的細胞老化，達到抑制癌細胞生長的效果，而p53會抑制端粒酶蛋白表現進而增強紫檀芪誘導的細胞老化現象。

The purpose of this study is to investigate whether pterostilbene (PT) inhibits the growth of lung cancer cell lines H460 and H1299 cells, and to investigate whether PT exerts effect through cellular senescence by telomerase inhibition. In addition, we also determine the role of p53 in regulating senescence mechanism by using a p53 stable expression cell line, H1299-p53+. Our results showed that PT can inhibit the growth rate of H460 and H1299 cancer cells at lower concentrations through induction of the cell cycle arrested in S phase. The colony formation assay showed lung cancers lost their proliferative ability after PT treatment. The treated cells showed the characteristics of cellular senescence such as positive staining of SA-β-gal, flatten morphology and formation of SAHF. PT-induced senescence correlated with increased DNA double strand breaks triggered by telomerase inhibition. The proteins expression of S phase related cyclins and cell cycle negative regulators were increased. The proteins level of cdc25A and telomerase were decreased. H460 and H1299-p53+ exhibited higher senescence and significant telomerase inhibition than H1299 when treated with PT. Overexpression of telomerase in H460 rescued the cellular senescence and DNA damage response triggered by PT. The underlying senescence mechanism induced by PT in our study involved DNA damage resulted from inhibition of telomerase activity and expression. Moreover, the inhibition of telomerase expression in H460 was p53-dependant, in which the p53 protein enhanced senescence in H460 cell. Taken together, we found a new anticancer mechanism of PT by inhibition of telomerase activity and expression in lung cancer cells. Induction of senescence by PT could be a novel and useful strategy of cancer therapy.

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