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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蕭寧馨(Ning-Shin Shaw) | |
| dc.contributor.author | Ya-Wei Lin | en |
| dc.contributor.author | 林亞葳 | zh_TW |
| dc.date.accessioned | 2021-06-15T11:12:09Z | - |
| dc.date.available | 2021-08-23 | |
| dc.date.copyright | 2016-08-23 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-22 | |
| dc.identifier.citation | 1. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of mammalian iron metabolism. Cell 2010; 142: 24-38.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48949 | - |
| dc.description.abstract | 鐵對細胞具有雙面效應，是細胞生長所必需，但也可經由芬頓反應 (fenton reaction) 產生活性氧ROS而對細胞造成毒性與傷害。鐵依賴性死亡ferroptosis是2003年新發現的細胞死亡模式，屬於非凋亡性細胞死亡模式的一種。透過鐵代謝衍生的脂質過氧化 (lipid peroxidation, LROS) 累積而造成細胞死亡，並且受細胞內信號路徑嚴密的調控。有別於以往發現之死亡形態，ferroptosis 的形態、生化標記或是基因特徵皆不同於apoptosis、necrosis以及autophagic。Ferroptosis的路徑包括抑制還原態穀胱甘肽 (GSH) 的合成和利用，造成GSH耗竭，最終產生脂質過氧化效應和細胞死亡；以上任一節點受到干擾，皆可能影響ferroptosis的發生。已知乳癌細胞具有堆積鐵的能力，其代謝鐵池增大有利於乳癌細胞生長，而且惡性程度越高，堆積鐵的能力越強。因此本研究的目的是探討ferroptosis對乳癌細胞的作用。利用三陰性乳癌細胞株MDA-MB-231對柳氮磺口比口定水楊酸 (sulfasalazine, SAS) 敏感以及強積鐵能力兩種特性，實驗設計誘導MDA-MB-231細胞死亡，利用專一性抑制劑ferrostatin-1並檢測ferroptosis 分子特徵，以及鐵相關抗氧化蛋白質NRF2、HO-1及ferritin (FTH) 的表現，並評估抗氧化礦物質硒和鋅化合物之影響。實驗結果確認SAS與鐵共同處理可使MDA-MB-231細胞發生ferroptosis，並受ferrostatin-1之抑制，細胞死亡前有ROS以及LROS量增加的現象。隨著SAS與鐵的劑量增加，細胞的NRF2以及FTH表現增加。硒可以抑制此死亡作用，可能機制是透過增加GPX4蛋白表現量；鋅增加SAS與鐵複合組細胞死亡，Zn-MT的增加無助於複合組細胞存活。 | zh_TW |
| dc.description.abstract | Iron plays dual roles in cells. It is essential for cell growth but also produce reactive oxygen species (ROS) via the Fenton reaction then inducing cell toxicity and damage. Iron-dependent cell death, ferroptosis, is a newly discovered non-apoptotic cell death mode in 2003. It is a regulated form of cell death driven by iron-induced lipid peroxide accumulation and regulation strictly by intracellular signaling pathway. The morphological, biochemical markers and genetic characteristics of ferroptosis are different from apoptosis, necrosis and autophagic. The mechanism of ferroptosis is inhibiting synthesis and utilization of reduced-glutathione (GSH) . Then, GSH depletion and lipid peroxide (LROS) accumulation lead to ferroptosis. Blockade of any steps is might prevent ferroptosis. Breast cancer cells have the ability of iron accumulation, which increases breast cancer cells growth. The higher malignancy degrees of breast cancer cells have the stronger ability of iron accumulation. Therefore, the purpose of this study is investigating the effect of ferroptosis on breast cancer cell. The study design is making use of the two characteristics of triple-negative breast cancer cell line MDA-MB-231 : sensitive to sulfasalazine (SAS) and strong ability of iron accumulation, to induce ferroptosis. We detect ferroptosis molecular characteristics, and the effects is blocked by specific inhibitors ferrostatin-1. Then, we analyze iron-related antioxidant proteins NRF2, HO-1 and ferritin (FTH) protein expression and assess the impact of the antioxidant mineral selenium and zinc compound in ferroptosis. The results show that combined group (SAS + iron) induce MDA-MB-231 cells ferroptosis, and ferrostatin-1 inhibit cell death. In addition, ROS and LROS are increased before cell death. The NRF2 and FTH protein expression levels are increased in a combined group dose-dependent manner. Finally, we found selenium can inhibit ferroptosis, and the mechanism may be through increasing the GPX4 protein expression. Zinc increase cell death in combined group and enhance Zn-MT protein expression, but Zn-MT does not contribute to prevent cell death. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T11:12:09Z (GMT). No. of bitstreams: 1 ntu-105-R99447010-1.pdf: 4568315 bytes, checksum: 477f7b402c6d5ace89c45e899a14ae8a (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 謝誌 i
中文摘要 ii Abstract iii 第一章 文獻回顧 1 第1節 鐵 1 1.1 人體鐵的平衡與分佈 1 1.2 組織之間鐵恆定的調節 3 1.3 細胞鐵恆定 3 1.4 調控之分子機制 3 第2節 乳癌 6 第3節 鐵與乳癌 8 3.1 鐵攝入量、血清鐵與乳癌相關性之研究 8 3.2 乳癌患者的鐵代謝變異 9 3.3 乳癌細胞堆積鐵之分子機制 9 第4節 非凋亡性細胞死亡模式：鐵依賴性死亡 (Ferroptosis) 12 4.1 細胞ferroptosis型態特徵 16 4.2 Ferroptosis抑制劑與檢測方法 17 4.3 誘發ferroptosis之機制 18 4.4 促進ferroptosis之因子 21 4.5 Ferroptosis與脂質代謝相關 23 第5節 Ferroptosis疾病動物模式之研究 25 5.1 神經退化性疾病 (Neurodegeneration) 動物模式 25 5.2 缺血性再灌流器官損傷與腎臟疾病模式 26 第6節 NRF2的生理功能 34 6.1 NRF2的結構與功能 34 6.2 NRF2調控之路徑：NRF2-ARE路徑 34 6.3 NRF2活性的調控 35 6.4 NRF2-ARE調控之下游蛋白 37 6.5 NRF2-ARE路徑在腫瘤形成的雙重作用 39 本論文研究目的與實驗設計 41 第二章 材料與方法 43 第1節 實驗細胞株 43 第2節 藥品與試劑 43 2.1 細胞培養 43 2.2 MTT試驗 44 2.3 細胞氧化壓力試驗 44 2.4 蛋白質定量與西方墨點法 44 2.5 enzyme-linked immunosorbent assay (ELISA) assay 45 第3節 試劑配製 46 3.1 細胞培養 46 3.2 細胞存活率分析 (MTT assay) 47 3.3 細胞氧化壓力試驗 47 3.4 蛋白質分析-西方墨點法 47 第4節 儀器 49 4.1 細胞觀察、培養與保存 49 4.2 MTT試驗、蛋白質測定 49 4.3 細胞氧化壓力試驗 49 4.4 西方墨點法 49 4.5 一般實驗儀器 49 第5節 實驗方法 51 5.1 細胞之解凍、培養、繼代與保存步驟 51 5.2 細胞存活率分析 (MTT assay) 51 5.3 細胞氧化壓力試驗 52 5.4 蛋白質定量分析 52 5.5 蛋白質分析-西方墨點法 (Western blot analysis) 53 5.6 ELISA assay 54 第6節 統計分析 54 第三章 實驗結果 56 第1節 水楊酸及鐵致乳癌細胞ferroptosis模式 56 結果 58 1.1 控制組 (C) 與抑制劑組 (ferro-1) 對乳癌細胞生長之影響。 58 1.2 FAC致乳癌細胞ferroptosis效應 58 1.3 SAS致乳癌細胞ferroptosis效應 59 1.4 複合組致乳癌細胞ferroptosis效應 59 討論 60 第2節 水楊酸及鐵致乳癌細胞氧化壓力的效應 65 結果 66 2.1 水楊酸、鐵及複合劑組對乳癌細胞cytosolic ROS表現量之效應 66 2.2 水楊酸、鐵及複合組對乳癌細胞lipid ROS表現量之影響 66 討論 67 第3節 Ferroptosis影響之抗氧化蛋白 71 結果 73 3.1 複合組對NRF2、HO-1、FTH效應 73 3.2 SFN及B對ferroptosis情形下抗氧化蛋白表現量之效應 75 3.3 Western Blot蛋白質序列稀釋補充實驗 80 討論 81 第4節 抗氧化礦物質selenium以及znic對ferroptosis之影響 83 結果與討論 86 4.1 Se對ferroptosis之影響 86 4.2 Zn對ferroptosis之影響 86 第四章 綜合討論 92 第1節 Ferroptosis研究里程碑 92 第2節 Ferroptosis待解的問題 94 2.1 鐵扮演在Ferroptosis扮演的角色 94 2.2 比較Ferroptosis、Oxytosis和Glutamate excitotoxicity 94 第3節 Se、Vitamin E與Cancer 97 第4節 細胞鐵狀態對癌細胞的影響 98 第五章 總結論 99 參考文獻 100 | |
| dc.language.iso | zh-TW | |
| dc.subject | 鐵依賴性死亡 | zh_TW |
| dc.subject | 鐵 | zh_TW |
| dc.subject | 乳癌 | zh_TW |
| dc.subject | 水楊酸 | zh_TW |
| dc.subject | Ferroptosis | en |
| dc.subject | Iron | en |
| dc.subject | Breast Cancer | en |
| dc.subject | Sulfasalazine | en |
| dc.title | 柳氮磺口比口定水楊酸與鐵誘發乳癌細胞MDA-MB-231鐵依賴性死亡初探 | zh_TW |
| dc.title | Ferroptosis Induction in Breast Cancer Cell Line MDA-MB-231 by Sulfasalazine and Ferric Ammonium Citrate | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 何佳安(Ja-an Ho),沈湯龍(Tang-Long Shen),蘇純立(Chun-Li Su),劉奕方(Yih-Fong Liew) | |
| dc.subject.keyword | 鐵依賴性死亡,鐵,乳癌,水楊酸, | zh_TW |
| dc.subject.keyword | Ferroptosis,Iron,Breast Cancer,Sulfasalazine, | en |
| dc.relation.page | 112 | |
| dc.identifier.doi | 10.6342/NTU201603493 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-08-22 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| 顯示於系所單位： | 生化科技學系 | |
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