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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 阮雪芬(Hsueh-Fen Juan) | |
dc.contributor.author | Hsin-Yi Chang | en |
dc.contributor.author | 張心儀 | zh_TW |
dc.date.accessioned | 2021-06-16T16:26:17Z | - |
dc.date.available | 2013-02-01 | |
dc.date.copyright | 2013-02-01 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-01-21 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63172 | - |
dc.description.abstract | 肺癌是全球癌症相關類別死因的首要原因。現行的標靶治療雖然能提供顯著的臨床反應、提升治療效果、且具有較少的副作用,但是這些標把藥物的治療效果仍然是有限的。因為多數患者隨著時間會對藥物產生耐藥性,導致癌症的復發或惡化。因此,尋找新的治療標靶分子可能可以達到這項未達治療標準的醫療需求。據報導發現粒線體F1Fo型三磷酸腺苷合酶會異位表達在癌細胞的細胞膜上,但其位於此處的功能尚不清楚。本研究中,我們發現表面型三磷酸腺苷合成酶和電子傳遞鏈皆於細胞膜上的呈現塊狀的分佈,這對於維持癌細胞增殖是相當重要的。應用表面型三磷酸腺苷合成酶抑制黃綠青黴素能夠誘導的細胞週期阻滯和抑制肺癌細胞的增殖及細胞的非貼附性生長。透過蛋白質體圖譜分析,我們發現黃綠青黴素的處理能誘導細胞發生未折疊蛋白反應以及轉譯起始因子eIF2α蛋白的磷酸化,進而觸發細胞生長的抑制作用。黃綠青黴素造成的eIF2α蛋白磷酸化可以透過降低PERK的表現、以及活性氧清除劑半胱氨酸所回復,建立了黃綠青黴素的處理會大量誘導活性氧分子的產生,透過PERK及eIF2α蛋白磷酸化而造成蛋白質轉譯的下降而導致細胞生長停滯的關係。因此,未折疊蛋白反應啟動和活性氧分子上升能互相正向加強,因此開啟了一個正向回饋迴路進而強化細胞生長的抑制。我們的研究結果釐清了表面型三磷酸腺苷合成酶在肺癌細胞的細胞膜的分子功能,並且進一步探討了其作為癌症治療上的潛力。 | zh_TW |
dc.description.abstract | Lung cancer is the leading cause of cancer-related death worldwide. Although targeted therapies can initiate dramatic clinical responses and offer significant therapeutic benefits and fewer side effects, the effectiveness of targeted therapies is currently limited because the majority of patients develop resistance over time, resulting in a relapse or worsening of the cancer. Thus, discovery of novel therapeutic markers might achieve the unmet clinical need. Ectopic expression of the mitochondrial F1Fo-ATP synthase on the plasma membrane has been reported to occur in cancer but whether it exerts a functional role in this setting remains unclear. Here we show that ectopic ATP synthase and the electron transport chain exist in a punctuated distribution on the plasma membrane of lung adenocarcinoma cells where it is critical to support cancer cell proliferation. Applying ATP synthase inhibitor citreoviridin induced cell cycle arrest and inhibited proliferation and anchorage-independent growth of lung cancer cells. Analysis of protein expression profiles after citreoviridin treatment suggested this compound induced the unfolded protein response (UPR) associated with phosphorylation of the translation initiation factor 2α (eIF2α), triggering cell growth inhibition. Citreoviridin-enhanced eIF2α phosphorylation could be reversed by siRNA-mediated attenuation of the UPR kinase PERK combined with treatment with the antioxidant N-acetylcysteine, establishing that reactive oxygen species (ROS) boost UPR after citreoviridin treatment. Thus, a coordinate elevation of UPR and ROS initiates a positive feedback loop that convergently blocks cell proliferation. Our findings reveal a molecular function for ectopic ATP synthase on the plasma membrane in lung cancer cells and prompt further study of its inhibition as a potential therapeutic application. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T16:26:17Z (GMT). No. of bitstreams: 1 ntu-102-D97b43006-1.pdf: 10158758 bytes, checksum: 9a8861eb372a0ef123bad96b6b26112c (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員會審定書 I
謝辭 II Abstract III 中文摘要 V Contents VI List of Figures X List of Table XII Abbreviation XIII Chapter 1 Introduction 1 1.1 Lung cancer 1 1.2 Targeted therapy 2 1.3 Ectopic ATP synthase 3 1.4 ATP synthase inhibitors 5 1.4.1 Substrate analogs 5 1.4.2 DCCD 5 1.4.3 Peptide inhibitors 6 1.4.4 Polyphenolic stilbenes 7 1.4.5 Oligomycin 7 1.4.6 Polyenic 2-pyrone derivatives 8 1.5 Endoplasmic reticulum stress and unfolded protein response 8 1.6 Motivation 10 Chapter 2 Materials and Methods 11 2.1 Cell culture 11 2.2 Drug treatment 11 2.3 Immunofluorescence staining 12 2.4 Analyzing ectopic ATP synthase expression by flow cytometry 13 2.5 Cell surface biotinylation 14 2.6 Preparation of purified plasma membranes proteins using affinity chromatography 14 2.7 Extracellular ATP generation assay 15 2.8 Flow cytometric detection of mitochondrial membrane potential 15 2.9 Flow cytometric detection of reactive oxygen species 16 2.10 Proliferation assay using xCELLigence system 16 2.11 MTS assays 17 2.12 Colony formation assay 17 2.13 DNA content analysis 18 2.14 Protein extraction 18 2.15 Two dimensional electrophoresis 19 2.16 Protein identification and mass spectrometry 20 2.17 Transfection of siRNA 21 2.18 Western blotting 21 2.19 Flow cytometric analysis of apoptosis using Annexin V/PI staining 22 2.20 Detection of oxygen consumption 22 2.21 Flow cytometric analysis of hypoxia by HIF-1α expression 23 2.22 Statistical analysis 23 Chapter 3 Results 24 3.1 ATP synthase is overexpressed in lung adenocarcinoma tissues 24 3.2 ATP synthase is expressed is expressed on the surface of lung cancer cells 24 3.3 Electron transport chain is located on the plasma membrane 26 3.4 ATP synthase inhibitors reduces the proliferation of lung cancer cells 27 3.5 Growth inhibition of citreoviridin is independent of EGFR 28 3.6 Citreoviridin does not affect the mitochondrial membrane potential of lung cancer cells 29 3.7 Citreoviridin induces G0/G1 phase arrest of lung cancer cells 30 3.8 Citreoviridin reduces anchorage-independent growth of lung cancer cells 30 3.9 Proteomic analysis identifies changes in CL1-0 cells with citreoviridin treatment 31 3.10 Functional analysis of proteomics data 32 3.11 Citreoviridin induces the unfolded protein response 33 3.12 Citreoviridin induces ROS dependent UPR 34 3.13 Citreoviridin-inhibited cell proliferation can be restored 35 3.14 Citreoviridin-induced UPR does not activate the apoptotic cascade 35 3.15 Citreoviridin induced ER stress is not caused by hypoxia 36 3.16 Application of citreoviridin in addictive treatment 37 Chapter 4 Discussion 38 Chapter 5 Future Work 43 Chapter 6 References 45 Table 63 Figures 67 Appendix A. Supplementary Figures 99 Appendix B. Curriculum Vitae 106 Appendix C. Publication 112 | |
dc.language.iso | en | |
dc.title | 肺癌細胞膜異位表達三磷酸腺苷合成酶阻斷後的分子機制探討 | zh_TW |
dc.title | Elucidating the Molecular Mechanisms of Ectopic ATP Synthase Blockade in Lung Cancer Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 王憶卿(Yi-Ching Wang),楊泮池(Pan-Chyr Yang),黃宣誠(Hsuan-Cheng Huang),徐駿森(Chun-Hua Hsu),陳健生(Chien-Sheng Chen) | |
dc.subject.keyword | 表面型三磷酸腺?合成?,未折疊蛋白反應,蛋白質體學,肺腺癌,黃綠青黴素, | zh_TW |
dc.subject.keyword | ectopic ATP synthase,unfolded protein response,proteomics,lung adenocarcinoma,citreoviridin, | en |
dc.relation.page | 112 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-01-21 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
顯示於系所單位: | 分子與細胞生物學研究所 |
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