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系統識別號 U0026-0812200913593819
論文名稱(中文) 1.探討三氧化二砷在乳癌細胞MCF-7所引發的細胞凋亡2.樟芝在thapsigargin對Huh-7細胞所引發內質網壓力之作用
論文名稱(英文) 1. Study On The As2O3-induced Apoptosis In MCF-7 Breast Cancer Cell 2. Effects Of Antrodia camphorata On Thapsigargin-induced Endoplasmic Reticulum Stress In Huh-7
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 95
學期 2
出版年 96
研究生(中文) 尤崧宇
研究生(英文) Sung-Yu Yu
電子信箱 t3694106@mail.ncku.edu.tw
學號 t3694106
學位類別 碩士
語文別 英文
論文頁數 79頁
口試委員 指導教授-黃暉升
口試委員-吳烘
口試委員-黃溫雅
中文關鍵字 三氧化二砷  內質網壓力  樟芝  細胞凋亡 
英文關鍵字 ER Stress  Antrodia camphorata  Apoptosis  p21  Arsenic trioxide 
學科別分類
中文摘要 Part 1.三氧化二砷已經廣泛的使用在治療急性前骨髓白血病的病人,它的機轉已在體內外試驗研究當中。從分離出來的骨髓癌、白血病、淋巴瘤細胞,以及膀胱、胃、食道、神經纖維、前列腺、卵巢的癌病細胞株,在三氧化二砷處理下都會引起細胞凋亡。然而,三氧化二砷引發細胞死亡的機制並不完全清楚。為了研究三氧化二砷在乳癌細胞的影響,首先我們偵測三氧化二砷引發MCF-7乳癌細胞株死亡的跡象。MTT assay的結果顯示在三氧化二砷處理72小時後,細胞生長的半數抑制濃度約為3μM,並且細胞凋亡的情形在流式細胞儀可偵測到。抑癌基因p21在癌症細胞的生長抑制上扮演重要的角色是眾所周知的事;然而最近的研究指出,磷酸化的Akt能夠磷酸化p21,並促使p21分布在細胞質,使其扮演一個對抗細胞凋亡的角色。所以我們分離細胞核質再用西方點墨法分析,發現在三氧化二砷處理下,p21從細胞質改變位置到細胞核,磷酸化Akt亦表現量降低。藉由共軛焦顯微鏡及流式細胞儀實驗,將細胞處理Akt抑制劑LY294002會造成p21改變位置到細胞核,並發生細胞凋亡。所以我們推論三氧化二砷所引發MCF-7細胞株的凋亡,是透過抑制Akt的磷酸化,進而降低p21留在細胞質所扮演的抗細胞凋亡之角色。Part 2.在台灣樟芝是廣為人知的傳統中藥,過去被用來作為解毒、治療腹瀉、腹痛、高血壓、以及皮癬。樟芝的提煉物具有抗氧化、清除自由基的功效,在體內可減清對肝臟的傷害。內質網壓力是起因於許多未摺疊的蛋白在內質網內堆積,並阻礙了內質網的功能;Thapsigargin (TG)是一個內質網壓力的促進因子,可造成內質網鈣離子的流失,並增加粒線體活性氧化物產生。在我們的研究裡,我們要探討在內質網壓力促進因子TG下,樟芝所具有的抗氧化功效。結果顯示在Huh-7肝細胞株中,樟芝可以降低TG與過氧化氫所引發的活性氧化物產生,代表樟芝具有抗氧化的功能。樟芝亦可以降低TG所產生的GRP78蛋白質表現,因此推測樟芝抗氧化的功能可改善細胞的內質網壓力;並且樟芝可減輕TG引起的細胞凋亡。因此,樟芝所具有的抗氧化及抗細胞凋亡的功效,可能更進一步提供來作為預防內質網壓力相關的疾病。
英文摘要 Part 1.Arsenic trioxide (As2O3) has been used in clinical trial of acute promyelocytic leukemia (APL) patients worldwide and its mechanisms are examined in both in vitro and in vivo studies. Freshly isolated cells from myeloma, leukemia and lymphoma, or cell lines from bladder, stomach, esophagus, neuroblastoma, prostate and ovary, all undergo apoptosis in vitro following treatment with As2O3. However, the mechanism of As2O3-induced cell death has not yet been clarified completely. To examine the effects of As2O3 in breast cancer cell, we firstly measured the cell death index of MCF-7 cells in response to As2O3. MTT assay showed that treatment with As2O3 for 72 hr induced growth inhibition, with IC50 value about 3 μM. It also induced apoptosis in MCF-7 cells upon As2O3 treatment by flow cytometry with propidium iodide staining. Cyclin dependent kinase inhibitor p21WAF1/CIP1 (p21) was well known to play an important role in cancer cell growth inhibition. However, recent reports showed that phosphorylated Akt can phosporylate p21 and lead to cytoplasmic localization of p21, which plays an important role in protecting cells against apoptosis. By using subcellular fractionation with Western blots, we also found that phosphorylated Akt was down-regulated, and then p21 was translocated from cytosol to nucleus upon As2O3 treatment for 4 hr. When the cells treated with the Akt inhibitor LY294002, the down-regulation of phosphorylated Akt also enhanced p21 translocation to nucleus and induced apoptosis by confocal microscopy and flow cytometry analysis. We conclude that As2O3 induced MCF-7 apoptosis via inhibition of Akt phosphorylation, which prevented accumulation of p21 in cytoplasm and lost its role in anti-apoptosis.Part 2.Antrodia camphorata (A. camphorata) is well-known in Taiwan as a traditional Chinese medicine. It has been used as a remedy for drug intoxication, diarrhea, abdominal pain, hypertension, and itchy skin. A. camphorata extract protects hepatic injury in vivo, by antioxidative and free radical scavenging activities. The endoplasmic reticulum (ER) stress is induced by accumulation of unfolded protein response leading to disrupt ER functions. Thapsigargin (TG), an ER stress inducer, causes ER Ca2+ release and increases mitochondrial ROS production. In this study, we tried to evaluate antioxidative effects of A. camphorata during TG-induced ER stress. The results showed that A. camphorata reduced TG or H2O2-induced ROS generation in Huh-7 cells, which indicate that A. camphorata has antioxidative effects to TG-induced ER stress. In addition, down-regulation of TG-induced GRP78 expression by A. camphorata suggests that the antioxidative effects could further improve the ER stress. Finally, TG-induced apoptosis in Huh-7 cells prevented by A. camphorata was also found. In conclusion, the antioxidative and anti-apoptotic effects of A. camphorata should be further exploited to be a promising preventive agent in ER stress-induced diseases.
論文目次 Part 1. Study On The As2O3-induced Apoptosis In MCF-7 Breast Cancer Cell
Abstract………………………………………...………………...1
中文摘要………………………………………………………………3
Introduction………………………………………..……………..4
Materials And Methods…………………………..………………7
Results……………………………………….…………………….14
Discussion………………………………….…………….……...20
References…………………………………..….………………….26
Figure Legends…………………………………….………..…..33
Part 2. Effects Of Antrodia camphorata On Thapsigargin-induced Endoplasmic Reticulum Stress In Huh-7
Abstract……………………………………………………….……44
中文摘要…………………………………………………….…….46
Introduction…………………………………………..…………47
Materials And Methods…………………………..…………..51
Results………………………………………….……………….54
Discussion………………………………………..……………..59
References……………………………………..……….……….63
Figure Legends........................................72
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