肺癌的多重抗藥性一直是肺癌治療上的一大困境。Rosiglitazone (ROSI)是PPARγ的活化劑，臨床上被用來治療及乳癌等。然而實驗室稍早的研究發現ROSI可藉由活化PPARγ促進非小細胞肺癌(H460)細胞中脂質小滴(Adiposome)及促進發炎因子的生成，進而提升保護(而非抑制)H460的存活。脂質小滴是脂肪或發炎細胞中會大量生成的一種胞器，已知具儲存中性脂肪和促發炎因子的功能，因此在脂肪代謝和發炎反應上扮演重要調控性的角色，但此胞器透過何種作用機轉保護NSCLC細胞的存活尚不清楚。石蓮花為一天然可食用之中草藥，其酒精或水萃物已知具有抗氧化、抗發炎及抗癌等作用，但其對非小細胞肺癌的存活是否具有抑制性及其抗肺癌的機轉是否和脂質小滴有關，從未報導過。本論文的研究目標，首先在釐清脂質小滴是否可調控和細胞生長和死亡相關的特定路徑，來保護H460細胞的存活，提升其對ROSI的抗藥性。另外，想進一步評估，WGP是否可抑制脂質小滴的生成及功能，進而抑制H460細胞之存活，提升細胞對ROSI的化療敏感性。研究策略包含: (一)探究ROSI提升之脂質小滴是否可透過TNFα抑制細胞週期的停滯、細胞凋亡、Parthanatos及提升自噬作用的發生，進而保護H460細胞之存活；(二)評估WGP是否可阻斷脂質小滴對特定死亡路徑的抑制，進而抑制H460細胞之存活。TNFα已知可自脂質小滴釋出並具有調控細胞週期停滯、凋亡、Parthanatos及自噬作用的功能(和細胞種類具有依存性)。研究方法主要是藉由MTT分析法、油紅O染色法、西方墨點法、Annexin V/PI染色、TUNEL染色、PI染色、ELISA和DNA fragmentation等方法，分別評估脂質小滴和WGP對各種細胞死亡路徑的調控。另外實驗中亦利用脂質小滴抑制劑(NS-398)進一步確認脂質小滴對細胞存活及死亡路徑調控的重要性；及外加TNFα的方式確認脂質小滴的功能是否經由釋放的TNFα所致。研究結果顯示ROSI(10μM；24h)不僅提升H460細胞之存活率，亦明顯提升細胞中脂質小滴的生成。透過脂質小滴抑制劑(NS-398)的干擾更進一步證明ROSI可透過提升脂質小滴來提升H460細胞的生長。ROSI提升的脂質小滴除可以抑制細胞週期的停滯(於G2/M階段)及Parthanatos的發生外，亦具有提升細胞自噬作用的功能，但對細胞凋亡不具影響性。而脂質小滴對前三者的調控均具TNFα依存性。研究中更首次證明WGP可顯著抑制經ROSI處理過之H460細胞中脂質小滴的生成，提升細胞凋亡及Parthanatos但抑制細胞自噬的發生，進而造成H460存活率的下降。而後三者的變化明顯和脂質小滴被WGP抑制具關連性。整體而言本論文的研究首次證實ROSI-提升之脂質小滴，可藉由釋放TNFα抑制細胞週期的停滯及Parthanatos的發生，並提升自噬作用，來提升H460細胞的生長。WGP則可藉由對脂質小滴的抑制，破壞ROSI對H460細胞之保護，降低細胞之存活率。上述結果除釐清為何ROSI無法成功用於治療NSCLC的原因外，更提出一新的發現證實WGP具有抑制脂質小滴的功能，其有助於抑制癌細胞的存活，降低其抗藥性，日後或可考慮為化療藥物的佐劑(致敏劑)用以降低化療藥物的使用濃度及可能的副作用。透過此研究，可進一步了解脂質小滴和WGP在癌症生物學的病理作用，為近期NSCLC的治療提供有價值的資訊。

The multiple drug resistance of lung cancer has been a major obstacle in the treatment of lung cancer. Rosiglitazone (ROSI) is a PPARγ agonist and clinically has been used to treat diabetes and breast cancer. Results from our early studies however, had shown that ROSI-activated PPARγ can stimulate adiposome formation to increase the growth of non-small cell lung cancer (NSCLC; H460) cells. Adiposomes are the main organelles for storage and turnover of neutral lipids as well as inflammatory mediators. The working mechanisms underlying the adiposome-increased growth of NSCLC cells were, however, unclear. The water extract of Chinese herbal Graptopetalum paraguayense (WGP) has been known to possess both anti-inflammatory and anti-cancer capabilities. Its impacts upon NSCLC and adiposome have never been reported before until now. The primary goals of the study were to know the working mechanisms underlying the adiposome-increased cell growth of non-small cell lung cancer (NSCLC) cells (H460) and to estimate the potential of WGP (the water extract of Chinese herbal Graptopetalum paraguayense) in inhibiting of adiposome formation and then growth of H460 cells. Experimental strategies of the study included: to determine could ROSI-induced adiposome act through TNFα to inhibit the cell cycle arrest, apoptosis and parthanatos but stimulate the autophagy to increase the growth or drug (ROSI) resistance of H460 cells; and to know could WGP block ROSI-induced adiposome formation to break the ROSI resistance of H460 cells. TNFα can be released from adiposome and has been reported to regulate cell cycle arrest, apoptosis, parthanatos and autophagy, in a cell-type dependent manner. Techniques applied in the study included, MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, Oil-red-O stain, Western blotting, AnnexinV/Propidium iodide (PI) stain, TUNEL stain, PI stain, ELISA and DNA fragmentation, chemical blocking assay using NS-398 and TNFα supplement assay. The results showed that ROSI(10 μM, 24 h) can significantly increase the growth and adiposome formation of H460 cells. ROSI-increased adiposomes appeared to play a critical role in the promotion of the growth of H460 cells, via inhibiting of the cell cycle arrest (at G2/M stage) and parthanatos and stimulating of the autophagy of H460 cells, in a TNFα-dependent manner. ROSI-increased adiposomes played no role in regulating of apoptosis of H460 cells. The results for the first time demonstrated that WGP can block ROSI-increased cell growth of H460 cells that was likely due to the WGP-inhibited adiposome formation and the subsequent inhibition of autophagy and stimulation of parthanatos of H460 cells. WGP also inhibited the apoptosis of H460 cells that appeared to be adiposome-independent. Novelty of the study is to show for the first time in cancer cells that ROSI-increased adiposomes can act through multiple ways, by modulating the cell cycle arrest, parthanatos and autophagy, to increase the growth of H460 cells. WGP can block ROSI-increased adiposome formation and then growth of H460 cells were also new suggesting that WGP may be used as an adjuvant in combination with chemotherapeutic drugs for NSCLC therapy. Through the study, the pathophysiological roles of adiposome and WGP in cancer biology have been further explored that could provide valuable information for the control of NSCLC in near future.

摘要 i
Abstract iii
目錄 v
圖表目錄 vii
第一章 前言 1
一、肺癌 1
二、肺癌與抗藥性 2
三、脂質小滴 3
四、細胞死亡路徑 4
五、石蓮花 6
六、研究動機與目標 6
第二章 材料與方法 8
一、藥品來源 8
二、細胞株培養 8
三、藥物處理 9
(一) 藥品溶解及稀釋 9
(二) Rosiglitazone（ROSI） 9
(三) NS-398 (脂質小滴抑制劑) 9
(四) Tumor necrosis factor-alpha (TNFα) 9
(五)石蓮花水萃物(WGP) 10
(六) MNNG (Parthanatos促進劑) 10
(七) 3-MA (自噬作用抑制劑) 10
四、細胞存活率分析(MTT assay) 11
五、油紅O染色(Oil red O staining) 11
六、西方墨點法(Western blotting) 11
(一)全蛋白質萃取 11
(二)細胞核和細胞質蛋白質萃取 12
(三)蛋白質濃度測定及備置 12
(四) SDS-PAGE的備置及電泳分析 12
(五)蛋白質轉漬(Transfer) 13
(六)免疫雜交反應及顯影 13
七、TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) 分析法 13
八、Annexin V /PI 染色分析 14
九、PI染色 PI/Flow cytometry分析 14
十、PARP-1活性分析 15
十一、DNA電泳分析(Agarose Gel Electrophoresis of DNA) 15
(一)、DNA 萃取 15
(二)、DNA濃度及純度的測定 16
(三)、瓊脂(Agarose)凝膠的製備 16
(四)、電泳分析及影像擷取 16
十二、統計分析 16
第三章 實驗結果 17
一、ROSI可顯著提升H460細胞之存活率 17
二、ROSI提升的脂質小滴具有促進細胞存活的功能 17
三、ROSI提升之脂質小滴可透過TNFα抑制細胞週期停滯於G2/M 18
四、ROSI提升之脂質小滴對H460細胞之凋亡均不具調控性 18
五、ROSI提升之脂質小滴可透過TNFα抑制Parthanatos的生成，而提升 細胞之存活 19
六、ROSI提升的脂質小滴可透過TNFα促進細胞自噬作用的生成，進而 保護H460細胞之存活 19
七、ROSI提升的脂質小滴亦明顯受到Autophagy的正回饋調控 20
八、WGP可抑制ROSI提升之脂質小滴的生成，進而抑制H460細胞存活. 20
九、WGP對H460細胞存活的抑制和細胞週期的停滯無關 21
十、WGP可促進H460細胞凋亡的發生，但可能和脂質小滴無關 21
十一、WGP和ROSI共存時，具有促進Parthanatos生成的影響力 21
十二、WGP可抑制ROSI提升的自噬作用 21
第四章 討論 23
一、脂質小滴不僅可保護正常細胞，亦可保護癌細胞的存活及發育 23
二、脂質小滴可藉由釋放TNFα抑制細胞週期的停滯(G2/M)和抑制細胞Parthanatos的發生，和促進細胞的自噬作用進而提升H460細胞之 存活 24
三、脂質小滴和自噬作用(Autophagyosome)間距相互正調控的關係 25
四、石蓮花(WGP)能抑制細胞中脂質小滴的生成，促進Parthanatos和抑制 細胞自噬作用進而降低H460細胞的存活 26
五、石蓮花(WGP)和NS-398之效能比較 26
第五章 圖與表 28
第六章 參考文獻 52

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