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系統識別號 U0026-2708201902225900
論文名稱(中文) Formosanin C 抑制肺癌細胞生長中autophagy及mitophagy扮演的角色
論文名稱(英文) Formosanin C suppresses lung cancer cell growth: the roles of autophagy and mitophagy
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 107
學期 2
出版年 108
研究生(中文) 朱曼菱
研究生(英文) Man-Ling Chu
學號 S46061024
學位類別 碩士
語文別 英文
論文頁數 52頁
口試委員 指導教授-劉校生
口試委員-蘇純立
口試委員-張志鵬
口試委員-藍昇輝
中文關鍵字 皂素  細胞自噬  粒腺體自噬  肺癌 
英文關鍵字 Formosanin C  Autophagy  Mitophagy  Lung cancer 
學科別分類
中文摘要 皂素是一種從台灣蚤休萃取出來的天然化合物並具有抗癌效果。先前文獻指出皂素可以誘使人類肺癌細胞進行細胞自噬並造成細胞凋亡,而在大腸癌細胞中發現會透過造成粒線體膜電位下降而造成細胞凋亡。膜電位下降是粒線體受損的一個訊號,因此這類的粒腺體會經由有選擇性的細胞自噬清除,這個過程又稱粒線體自噬。目前尚未知道皂素是否可以在細胞中引起粒線體自噬。我們發現細胞經過皂素處理後,LC3 II的表現量在七十二小時內持穩定增高,這代表細胞自噬的過程是異常的。因此,本篇的研究目的是釐清在細胞中皂素對於細胞自噬、粒線體自噬的效果和他們之間的關係,以及他們在皂素相關的細胞死亡中所扮演的角色。本篇所使用的細胞株為人類肺癌細胞A549。首先,我們驗證隨著處理的濃度增高、時間增強,皂素抑制癌細胞生長的效果越好。在施藥二十四小時後使一半的細胞死亡的濃度為4µM,接著我們在整個實驗中皆以這個濃度對細胞施藥。我們發現皂素和CQ (自噬小體和溶體融合的抑制劑)具有相似的效果,都可阻斷amiodarone(細胞自噬反應誘導劑)所引起的細胞自噬的過程。因此,我們可以證明皂素是細胞自噬的阻斷劑。此外,我們發現粒腺體的蛋白質存在於純化的自噬小體中,同樣地,LC3 II也存在於純化的粒腺體當中。我們進一步發現粒腺體和自噬小體是透過粒線體外膜上的BNIP3連接,BNIP3是已被報導的粒腺體自噬受器。PINK1會透過磷酸化Parkin去促進的粒線體自噬反應。皂素處理後,細胞中Parkin磷酸化的程度增加,這意味著皂素能夠誘使粒線體自噬發生。然而,皂素卻對細胞中粒腺體蛋白質的含量沒有影響,因此我們認為皂素引起的粒腺體自噬也是受到阻斷的。接著我們發現將細胞以皂素和自噬反應誘導劑或粒腺體自噬反應誘導劑一同處理後,細胞的生長速度相較於皂素單一處理組別明顯被大幅抑制。最後,我們探討在皂素以及CQ的存在下粒線體自噬對於細胞的影響,我們發現不管是皂素或CQ的組別,粒腺體自噬都可以加強抑制細胞生長。因此我們可以知道,細胞自噬反應和粒腺體自噬反應對於A549細胞株都是有細胞毒性的。綜上所述,我們是第一個證實皂素是細胞自噬及粒線體自噬阻斷劑的實驗室。促進細胞自噬和粒線體自噬可以加強皂素的抗癌效果,因此我們認為將皂素與細胞自噬或粒線體自噬誘導劑合併使用能有效地提升癌症治療的效果。
英文摘要 Formosanin C (FC) is a natural compound extracted from Paris formosana Hayata with anti-cancer activity. Zhang et al. reported that FC induces both autophagy and apoptosis in human lung cancer cells. Furthermore, Won et al. reported that FC‐induced apoptosis requires depolarization of mitochondrial membrane potential (MMP). Depolarized mitochondria engulfed by the autophagosome for degradation is defined as mitophagy. However, it is not known whether FC can induce mitophagy. We found that FC treatment of A549 cells leads o steady increase of LC3 II levels until the end of investigation (72 hr), indicating aberration of autophagic flux. Therefore, we aimed to clarify the effect of FC on autophagy, mitophagy, the relationship between these two events and the roles of autophagy and mitophagy in FC-related cell death. Human lung cancer cell line A549 was used as our cell model. Initially, we verified that FC inhibits A549 cell growth in a dose- and time-dependent manner by MTT assay and 4 µM FC (IC50 at 24 hr) was used in this entire study. We reveal that amiodarone (an autophagy inducer)-induced autophagic flux was blocked by FC as well as chloroquine (CQ, a known fusion blocker of autophagosome and lysosome) demonstrated by Western blotting and IFA analysis, indicating that FC is a blocker not an inducer of autophagy. We further found mitochondrial protein COX IV in the purified autophagosome and autophagosome protein LC3 II in the purified mitochondrion. Furthermore, we detected the binding of BNIP3, a mitophagy receptor, and LC3 II by immunoprecipitation after FC treatment for 24 hr. These data indicate BNIP3 links mitochondrion and autophagosome. PTEN-induced kinase (PINK1) phosphorylates Parkin to initiate mitophagy. FC also increased the phosphorylation of Parkin (p-Parkin) on Ser65. However, FC shows no effect on mitochondrial protein COX IV expression, indicates mitophagy is impaired. Altogether, FC seems to be able to initiate mitophagy, however, mitophagy progression was abrogated possibly by FC blockage of fusion of autophagosome and lysosome. Finally, we reveal both inducers of autophagy and mitophagy increased FC-related cell death. Furthermore, we also reveal that mitophagy enhanced the anti-tumor effect in the presence of FC or CQ. These data imply that autophagy and mitophagy are cytotoxic to FC-treated A549 cells. In summary, we are the first to reveal that FC blocks both autophagic and mitophagic flux in A549 cells. Autophagy and mitophagy play a promoting role in FC-related cell death. Combination of FC and autophagy or mitophagy inducers may enhance the anti-cancer activity. Therefore, it has the potential to become an effective treatment strategy.
論文目次 中文摘要 2
Abstract 4
致謝 6
Index 7
Abbreviation 8
Introduction 9
I. Lung cancer 9
II. Formosanin C 9
III. Autophagy 9
IV. Autophagy and cancer 10
V. Formosanin C and autophagy 11
VI. Mitophagy 12
VII. Mitophagy and anti-cancer strategy 13
VIII. Specific aims 13
Materials and methods 14
I. Cell lines and Media 14
II. Cell proliferation 14
III. Cell death analysis 14
IV. Western blotting 14
V. Immunofluorescent staining 15
VI. Mitochondrial isolation 15
VII. Autophagosome purification 15
VIII. Immunoprecipitation (IP) 16
Results 17
Discussion 21
References 24
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