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研究生:黃翠琴
研究生(外文):Tsui-Chin Huang
論文名稱:ATP合成酶─具潛力之乳癌治療標靶分子
論文名稱(外文):ATP synthase: A potential target for breast cancer therapy
指導教授:阮雪芬阮雪芬引用關係
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:分子與細胞生物學研究所
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:2009
畢業學年度:97
語文別:英文
論文頁數:107
中文關鍵詞:標靶治療蛋白質體學分析ATP合成酶aurovertin B乳癌細胞凋亡細胞週期停止
外文關鍵詞:targeting therapyproteomic analysisATP synthaseaurovertin Bbreast carcinomaapoptosiscell cycle arrest
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將標靶藥物治療專一的特性應用於癌症的治療上,可提高療效,縮短療程,並降低傳統化學治療進行時所產生的副作用。本篇研究分析了乳癌病理組織的蛋白質表現圖譜,且發現癌化組織具有ATP合成酶的高度表現。以往認為ATP合成酶只會出現於粒線體內膜上,然而在本研究中發現,ATP合成酶會表現於乳癌細胞表面,縱使其功能未知,仍舊可以做為辨識癌細胞的標靶分子。當給予ATP合成酶抑制劑時,乳癌細胞會受到毒殺,但對於給予相同劑量抑制劑的正常細胞則無影響。本篇研究發現,ATP合成酶抑制劑會經由細胞凋亡的路徑抑制乳癌細胞生長,並導致細胞週期停止於G0/G1期。此外,本篇研究亦指出,ATP合成酶抑制劑會活化caspase參與的訊息傳遞路徑,進而誘導細胞凋亡。這項發現提供了另一類的抗癌化合物─ATP合成抑制劑─可做為治療乳癌及其他癌症的標靶藥物。
Targeting therapy is one of the most promising approaches to increase the efficiency of anticancer treatment, thus the investigation into potential targets has become an important research topic in cancer therapy. In this study, we carried out a proteome-based analysis on human breast cancer tissues to probe into the tumor-specific protein expression in breast carcinoma. Conventionally, ATP synthase was believed to be localized in the mitochondrial inner membrane and served as an energy protein complex. Our study indicated that ATP synthase was abundant in tumor tissues and was also present on the plasma membrane surface of breast cancer cells. Aurovertin B, an ATP synthase inhibitor, has strong inhibition on the proliferation of several breast cancer cell lines, but little influence on the normal cell line MCF-10A. Aurovertin B inhibits proliferation of breast cancer cells by inducing apoptosis and arresting cell cycle at the G0/G1 phase. Furthermore, aurovertin B induces the cytotoxic effects in a caspase-dependent manner. This study showed that aurovertin B can be used as an anticancer agent and may be exploited in cancer chemotherapy.
Contents
口試委員會審定書 I
Acknowledgements III
Abstract V
中文摘要 VII
Contents IX
List of Figures XII
List of Tables XIV
Chapter 1 Introduction 1
1.1. Breast cancer 1
1.1.1 Stages of breast cancer 1
1.2 Targeting therapy 5
1.3 Biomarker 6
1.4 Proteomics 6
1.5 Structure bioinformatics 8
1.6 F1FO ATP synthase 9
1.7 ATP synthase inhibitors 10
1.8 Apoptosis 12
1.9 Caspase cascade 14
Chapter 2 Specific Aims 15
Chapter 3 Materials and Methods 16
3.1 Breast cancer specimens and protein extraction 16
3.2 Two dimensional gel electrophoresis (2DE) 16
3.3 In-gel digestion 17
3.4 Protein identification and database searching 18
3.5 Homology modeling 19
3.6 Docking simulation 20
3.7 Western blotting 20
3.8 Cell culture 21
3.9 Flow cytometry 21
3.10 Confocal microscopy 22
3.11 MTT assay 22
3.12 Cell cycle analysis 23
3.13 Annexin V-FITC/PI analysis 23
3.14 DAPI staining 24
3.15 Statistical analysis 24
Chapter 4 Results 25
4.1 Identification of potential targeting proteins 25
4.2 β subunits of ATP synthase localized on the surface of MCF-7 cells 26
4.3 ATP synthase homology modeling and docking simulation 26
4.4 Proliferation inhibition of MCF-7 by F1-targeting ATP synthase inhibitors 28
4.5 Cytotoxicity of aurovertin B to breast cancer cells 28
4.7 Aurovertin B induced apoptosis in human MCF-7 cells 30
4.8 Aurovertin B triggered caspase cascade responsible for apoptosis 31
Chapter 5 Discussion 32
Chapter 6 Conclusion 46
Chapter 7 Future work 47
Reference 49
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