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研究生:馬格帝
研究生(外文):Ahmed Magdy Abu El-Fotouh
論文名稱:砷對A549肺腺癌細胞自噬作用與一氧化氮之探討
論文名稱(外文):The role of autophagy and nitric oxide in arsenite-induced cytotoxicity and genotoxicity in lung adenocarcinoma A549 cells
指導教授:楊嘉鈴
指導教授(外文):Yang, Jia-Ling
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:63
中文關鍵詞:肺癌自噬一氧化氮
外文關鍵詞:Lung cancerArsenicAutophagyNitric oxide
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哺乳類細胞接觸到類金屬砷導致細胞毒性以及基因上的損害,但在砷誘導後產生的自噬作用機轉尚未清楚。自噬作用在演化上具有高度保守性,其自噬細胞代謝過程中會將受損的胞器或是異常的蛋白降解,適當的自噬作用是為了讓細胞免於傷害,過多現象產生反而容易造成細胞死亡。另外也發現一氧化氮在調節癌細胞存活與死亡扮演很重要之角色。因此,進而希望能夠釐清砷在A549肺腺癌引起的自噬作用以及氧化作用。為了觀察到自噬作用是否存在A549肺腺癌,使用吖啶橙染色 (acridine orange staining, AO staining)判定到自噬泡的生成,並以西方點墨法(western blot)觀察微管結合蛋白第三型輕鍊-I(LC3-I)的轉換,形成 LC3-II的堆積。藉由螢光顯微鏡證實以砷誘導細胞產生自噬作用,更進一步驗證先前的實驗。此外,以細胞自噬抑制劑如spautin-1, chloroquine, or 3-methyladenine進行細胞毒殺試驗(MTT assay)以及癌細胞群落形成能力試驗(colony forming ability assay),發現加入細胞自噬抑制劑反而導致了癌細胞的死亡,推測細胞自噬作用在含有砷的環境壓力下為保護細胞的機制。另一方面,為了更深入了解砷刺激細胞後,一氧化氮是如何影響細胞存活,以不同的調節劑觀察一氧化氮。從實驗的結果,我們認為一氧化氮的生成是為了提高細胞存活對抗砷毒性。最後藉由細胞形成微核(micronuclei)的能力探討自噬作用與對基因的潛在影響,也進一步驗證自噬作用與一氧化氮是避免基因受到砷毒害而產生的機制以維持基因之穩定性。

It is well known that arsenic induces cytotoxicity and genotoxicity in mammalian cells, and arsenic-induced autophagy was clearly demonstrated. Autophagy is an evolutionarily conserved, catabolic process that maintains cellular homeostasis by regulating organelles and proteins turnover and, meantime, induces autophagic cell
death. In line with this, nitric oxide is also known for its dual role in cancer cells by regulating cell survival and cell death. We have recently identified that arsenite can induce nitric oxide progression in A549 lung adenocarcinoma cell line. So, I focused my thesis studies on understanding the role of autophagy and nitric oxide mediated by arsenite in cytotoxicity and genotoxicity in A549 non-small cell lung cancer cells. To accomplish the previously stated goal, I have performed the acridine orange staining assay to detect the activation of autophagosome formation, and used western blot technique to monitor the conversion of LC3B-I to LC3B-II, which is a key marker protein for autophagy induction. The preliminary results from fluorescent microscopy have been further validated by western blot analysis, which confirmed the role of arsenite in inducing autophagy. Moreover, the results obtained from MTT assay and colony forming ability assay showed that treating the cells with autophagy inhibitors, such as spautin-1, chloroquine, or 3-methyladenine, enhanced arsenite-induced cell death suggesting that autophagy has a protective role under arsenite stress. In addition, to study the role of nitric oxide in regulating cell viability under arsenite treatment; I treated the cells with nitric oxide modulators, such as PTIO, 1400W, and GSNO, and the results obtained from MTT assay suggested that NO has a prosurvival role against arsenite toxicity. Moreover, investigating the potential function of autophagy and nitric oxide in genome stability via assessing the ability of the cells to form micronuclei was also conducted, and the results suggested that arsenite-induced
autophagy is required for suppressing genotoxicity following arsenite exposure.
Interestingly, the results obtained from micronucleus assay suggested that nitric oxide is critically required for genome stability in normal and stressful conditions.
DEDICATION …………………...…………………………………..………………. I
ACKNOWLEDGEMENT ……………..……………………………………………. II
ABBREVIATIONS…………………………………………………………………. III
ABSTRACT ……………………………………………………………...………… IV
CHAPTER
1. Chapter 1. Introduction ………………………………………………………. 1
1.1. Lung cancer …………..…………………………………………………… 1
1.1.1. Lung cancer definition and statistics ……………………...…………. 1
1.1.2. Lung cancer classification …...………………………………………. 1
1.1.3. Smoking and lung cancer incidence …………………………………. 2
1.1.4. Pathogenesis of lung cancer: molecular mechanisms and genetic mutations ……………..…………………………………………………………. 2
1.1.5. Etiology of lung cancer ……………………………………………… 3
1.1.6. Signs and symptoms of lung cancer ……………….………………… 3
1.1.7. Lung cancer tests and diagnosis ………….………………………….. 3
1.1.8. Lung cancer staging (TNM) …………………………………………. 4
1.2. Arsenic ….………………………………………………………………… 4
1.2.1. Definition ……………………………………………………………. 4
1.2.2. Arsenic sources ……………………..……………………………….. 5
1.2.3. Arsenic and arsenic compounds …..…………………………………. 6
1.2.4. Arsenic toxicity …………..………………………………………….. 7
1.2.5. Arsenic effects on laboratory animals ……………………………….. 7
1.2.6. Human exposure to arsenic and health effects ...…………………….. 8
1.2.7. Arsenic and cancer development …….………………………………. 9
1.2.8. Therapeutic effects of arsenic ..………………………………………. 9
1.3. Autophagy .………………………………………………………………. 10
1.3.1. Overview of autophagy .……………………………………………. 10
1.3.2. The autophagy machinery ………………………………………….. 10
1.3.3. Autophagy regulation and cancer ...………………………………… 12
1.3.4. Autophagy inhibitors ………..……………………………………… 12
1.4. Nitric oxide ……….……………………………………………………… 14
1.4.1. Overview of nitric oxide ….………………………………………… 14
1.4.2. Nitric oxide synthases ………..…………………………………….. 14
1.4.3. Nitric oxide and lung carcinogenesis …….………………………… 15
1.5. Aims of the study ……...………………………………………………… 15
2. Chapter 2. Material and methods ...………………………………………… 16
2.1. Reagent and antibodies ...………………………………………………… 16
2.2. Reagent preparation and storage …...……………………………………. 16
2.3. Cell culture …………….………………………………………………… 16
2.4. Arsenite treatment …..…………………………………………………… 17
2.5. Cell viability assays ……………………………………………………… 17
2.6. Clonogenic assay …...……………………………………………………. 18
2.7. Cytokinesis-block micronucleus assay ...………………………………… 19
2.8. Flow cytometry analysis of nitric oxide production ….………………….. 19
2.9. Cell lysate extraction and preparation …………………………………… 19
2.10. Western blot analysis .……………………………………………………. 20
2.11. Acridine orange staining analysis by fluorescence microscope …...…….. 21
2.12. Statistical analysis ….……………………………………………………. 21
3. Chapter 3. Results …………………………………………………………… 22
3.1. Arsenite induces autophagy in lung adenocarcinoma A549 cells …………… 22
3.2. Autophagy inhibitors enhance cell death in arsenite-treated A549 cells ......… 22
3.3. Autophagy inhibitors reduce colony-forming ability in arsenite-treated A549 cells ……………...…………………………………………………………… 23
3.4. Arsenite induces nitric oxide (NO) generation in A549 cells ……………..…. 23
3.5. NO inhibitors increase arsenite-induced cell death in A549 cells ...….……… 24
3.6. Autophagy inhibitors increase arsenite-induced genotoxicity ………….……. 24
3.7. Nitric oxide counteracts genome instability induced by arsenite stress in A549 cells ...………………………………………………………………………… 25
4. Chapter 4. Discussion .………..……………………………………………… 26
5. Chapter 5. Reference .………...……………………………………………… 31
6. Figures …………...…………………………………………………………… 43
6.1. Figure 1.Arsenite induces autophagy in A549 lung adenocarcinoma cells ..… 43
6.2. Figure 2. Autophagy inhibitors enhance arsenite-induced cell death …….….. 45
6.3. Figure 3. Autophagy inhibitors enhance arsenite-induced cytotoxicity …..…. 47
6.4. Figure 4. Validation of nitric oxide (NO) induction following arsenite exposure …………………………………...…………………………………. 49
6.5. Figure 5. Effect of NO modulators on arsenite-induced cell death …..……… 50
6.6. Figure 6. Autophagy inhibitors increase genotoxicity induced by arsenite in A549 cells ...……….…………………………………………………………. 52
6.7. Figure 7. Effect of NO modulators on arsenite-induced genotoxicity .………. 54

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