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研究生: 曾銀秋
Tseng, Yin-Chiu
論文名稱: 三氧化二砷經由刺激內質網壓力與抑制泛素-蛋白酶體系統作用誘發人類惡性肉瘤細胞計畫性死亡之探討
Arsenic trioxide induces programmed cell death through stimulation of ER stress and inhibition of ubiquitin-proteasome system in human sarcoma cells
指導教授: 王應然
Wang, Ying-Jan
學位類別: 碩士
Master
系所名稱: 醫學院 - 環境醫學研究所
Department of Environmental and Occupational Health
論文出版年: 2012
畢業學年度: 100
語文別: 中文
論文頁數: 80
中文關鍵詞: 惡性肉瘤三氧化二砷蛋白酶體抑制劑內質網壓力細胞凋亡自體吞噬
外文關鍵詞: Sarcoma, arsenic trioxide, proteasome inhibitor, ER stress, apoptosis, autophagy
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  • 惡性肉瘤 (sarcoma)是一種罕見的癌症,具有侵略性、抗藥性,和高度地轉移性,並且治療效果差、治癒率低。因此,如何改善治療策略而有效地殺死癌細胞是目前研究的重點。許多研究發現三氧化二砷不僅會誘發細胞凋亡 (apoptosis),亦可誘發細胞自體吞噬 (autophagy)來造成癌細胞死亡。有文獻指出細胞內活性氧物種 (reactive oxygen species, ROS)的累積、內質網壓力 (endoplasmic reticulum stress, ER stress)的刺激作用,或泛素蛋白酶體系統 (ubiquitin-proteasome system, UPS)的抑制作用會誘發細胞凋亡和自體吞噬。因此,本研究的目的為探討三氧化二砷是否可經由內質網壓力刺激作用和泛素蛋白酶體系統抑制作用來調控人類惡性肉瘤細胞株HOS (骨肉瘤細胞株) 與HT1080 (纖維肉瘤細胞株)計畫性細胞死亡模式,而達到殺死癌細胞的效果。本篇研究以HOS與HT1080兩株惡性肉瘤細胞進行實驗,在不同時間及劑量下以三氧化二砷處理後,利用Trypan blue分析細胞存活率,使用流式細胞儀分析細胞週期,並藉由Annexin V分析早期細胞凋亡。利用acridine orange染色,再以螢光顯微鏡觀察酸性小泡 (AVOs)。以酵素免疫微盤分析儀偵測細胞內鈣離子濃度變化與20S蛋白酶體活性,並利用西方墨點法測定內質網壓力、細胞凋亡和自體吞噬的相關蛋白表現變化。另一方面也利用核醣核酸干擾技術抑制內質網壓力指標IRE1的表現及後續早期細胞凋亡與自體吞噬的改變。在動物實驗方面,利用HT1080細胞株的腫瘤異種移植模式來探討三氧化二砷合併蛋白酶體抑制劑 (MG-132)的治療效果。實驗結果顯示處理三氧化二砷能有效地抑制HOS和HT1080兩株細胞的生長,並且皆會造成細胞週期G2/M期的停滯,以及增加細胞凋亡和自體吞噬的百分比。此外,經三氧化二砷處理後,兩株細胞中內質網壓力指標IRE1、自體吞噬指標LC3-II及細胞凋亡指標cleaved-caspase-3的表現量皆有增加的趨勢。然而另一內質網壓力指標p-eIF2α的表現量則為下降。此外,三氧化二砷皆會抑制HOS 和HT1080細胞中20S蛋白酶體活性。在細胞訊息途徑中發現經三氧化二砷處理下磷酸化的Akt、mTOR的蛋白表現量下降,而磷酸化的AMPK、p38與JNK蛋白表現量增加,表示Akt/mTOR途徑受到抑制,以及AMPK、p38與JNK途徑受到活化。然而在HOS細胞中磷酸化的ERK蛋白表現量受到抑制,HT1080細胞中則磷酸化的ERK蛋白表現量增加。利用核醣核酸干擾技術抑制內質網壓力指標IRE1的表現會提高細胞存活率,以及降低細胞凋亡和自體吞噬的百分比。此外,我們發現HT1080細胞株合併使用三氧化二砷和MG-132 (蛋白酶體抑制劑)會透過誘發細胞凋亡和自體吞噬而有協同毒殺細胞作用。在皮下注射HT1080細胞株的SCID小鼠動物實驗結果中可發現合併處理組別可顯著抑制腫瘤生長。綜合以上結果可知,在HOS細胞中,三氧化二砷會抑制泛素蛋白酶體系統作用及誘發內質網壓力指標IRE1所調控的細胞凋亡和自體吞噬,並且也藉由抑制Akt/mTOR途徑和ERK表現,以及活化JNK和p38來誘導自體吞噬和細胞凋亡反應。而在HT1080細胞中,三氧化二砷亦會抑制泛素蛋白酶體系統作用與誘發內質網壓力指標IRE1所調控的細胞凋亡和自體吞噬,並且也經由抑制Akt/mTOR途徑和活化JNK、p38和ERK表現來誘導自體吞噬和細胞凋亡反應。另外,此研究亦證明三氧化二砷合併蛋白酶體抑制劑可作為纖維肉瘤之新的治療策略。

    Sarcoma is a rare cancer type with characteristics of aggressive, drug-resistant and highly metastasis. In clinical, the efficiency of therapy is pretty low. Thus, there is a need to find a new therapeutic strategy and enhance the therapeutic efficiency of sarcoma. It has been reported that arsenic trioxide (ATO) not only induced apoptosis but also autophagy in a variety of cancer cells. Accumulation of reactive oxygen species (ROS), induction of endoplasmic reticulum stress (ER stress), or inhibition of ubiquitin-proteasome system (UPS) were suggested to trigger with apoptosis and autophagy. The main purpose of this study was to investigate whether the anticancer effect of arsenic trioxide-induced programmed cell death is through stimulation of ER stress and inhibition of ubiquitin-proteasome system in human sarcoma cells, and which mechanism contributes to this effect was also examined. This study applied two sarcoma cell lines included osteosarcoma (HOS cells) and fibrosarcoma (HT1080 cells). Those cells were treated with different concentrations of ATO in a variety of time point. Cell viability was determined by trypan blue. Cell cycle distribution and early apoptosis with Annexin V-FITC apoptosis detection kit were analyzed by flow cytometry. In order to observe the appearance of acidic vesicular organelles (AVOs), an important characteristic of autophagy, cells were stained with acridine orange and visualized by fluorescence microscopy. Intracellular Ca2+ level and 20S proteasome activity were analyzed by ELISA Reader. Ultrastructure and ER dilation of HOS and HT1080 were analyzed by electron microscopy. The ER stress-, apoptosis-, and autophagy-associated proteins expression were detected by immunoblotting. In addition, RNA interference technology with IRE1-targeted shRNA was also applied in this study. In in vivo study, therapeutic efficacy of ATO and proteasome inhibitor (MG-132) in HT1080 malignant fibrosarcoma xenografts after treatment was assessed.The results indicated that ATO significantly inhibited cell proliferation. ATO treatment induced a significantly prolonged G2/M arrest and consequently enhanced the percentage of apoptosis and autophagy in HOS and HT1080 cells. We found that ATO increased the level of ER stress-associated protein IRE1, LC3-II (autophagy-related protein) and cleaved-caspase-3 (apoptosis-related protein). Whereas, ATO treatment downregulated p-eIF2α protein levels, an ER stress protein. In addition, ATO caused inhibition of 20S proteasome activity in HOS and HT1080 cells. We also found that ATO significantly decreased the phosphorylation of Akt and mTOR and increased the phosphorylation of AMPK, p38, and JNK in HOS and HT1080 cells. Whereas, ATO inhibited the expression of ERK in HOS cells and increased the expression of ERK in HT1080 cells. Transfection with IRE1 shRNA significantly decreased cytotoxicity, autophagy and apoptosis compared with mock treatment in both sarcoma cells. Furthermore, combined treatment of ATO and MG-132 showed synergistic effect through induction of apoptosis and autophagy in HT1080 cells. In in vivo study, the combined treatment of ATO and MG-132 significantly reduced the tumor volume in HT1080-bearing SCID mice. Taken together, ATO induced apoptosis and autohagy in HOS cells through inhibition of UPS, induction of ER stress, inhibition of Akt/mTOR and ERK signaling pathway and activation of JNK and p38 signaling pathway. ATO induced apoptosis and autophagy in HT1080 cells through inhibition of UPS, induction of ER stress, inhibition of Akt/mTOR and activation of ERK, JNK and p38 signaling pathway. In conclusion, this study demonstrated that a combination of ATO and proteasome inhibitor could be a new potential therapeutic strategy for the treatment of fibrosarcoma.

    第一章、 序論……………………………………………………………1 第二章、 文獻回顧…………………………………………………………2 第一節、 惡性肉瘤 (Sarcoma)………………………………………………………2 第二節、 骨肉瘤 (Osteosarcoma)……………………………………………………4 第三節、 纖維肉瘤 (Fibrosarcoma)…………………………………………………6 第四節、 三氧化二砷 (Arsenic trioxide, As2O3)……………………………………6 第五節、 內質網壓力 (Endoplasmic reticulum stress)…………………….10 第六節、 泛素蛋白酶體系統 (Ubiquitine proteasome system)……………12 第七節、 細胞凋亡 (Apoptosis)與自體吞噬 (Autophagy)……………………..14 第三章、 研究目的………………………………………………………..17 第四章、 研究架構…………………………………………………………..18 第五章、 研究材料與方法……………………………………………………..21 第一節、 實驗材料…………………………………………………………….21 第二節、 實驗儀器…………………………………………………………….26 第三節、 研究方法與實驗步驟……………………………………………….27 In vitro……………………………………………………………………………….27 一、 細胞株與細胞培養…………………………………………………….27 二、 細胞週期分析……………………………………………………….28 三、 自體吞噬 (Autophagy)分析……………………………………..29 四、 早期細胞凋亡 (Early apoptosis)分析…………………………29 五、 Acridine orange螢光染色現象………………………………………30 六、 穿透式電子顯微鏡 (TEM)……………………………………………………30 七、 西方點墨法 (Western blotting)………………………………………………..30 八、 偵測細胞內鈣離子………………………………………………….32 九、 蛋白酶體活性 (Proteasome activity)………………………………………….33 十、 干擾性核醣核酸 (RNA interference;RNAi)…………………………………33 十一、 合併藥物效應分析 (Drug interaction analysis)………………………33 十二、 統計分析………………………………………………………….34 In vivo………………………………………………………………………………..34 NOD/SCID mice腫瘤誘發實驗…………………………………34 一、 Mice…………………………………………………………………………….34 二、 腫瘤誘發給藥…………………………………………………….35 三、 蘇木紫伊紅染色 (Hematoxylin & Eosin Staining)………………………36 四、 組織免疫染色 (Immunohistochemistry)…………………………........36 五、 統計分析…………………………………………………………………38 第六章、 實驗結果………………………………………………………………39 第一節、 三氧化二砷對HOS與HT1080細胞的劑量及時間效應……………39 第二節、 三氧化二砷對HOS與HT1080細胞的細胞週期變化…………………39 第三節、 探討三氧化二砷對HOS與HT1080細胞凋亡與自體吞噬的表現……40 第四節、 分析三氧化二砷對HOS與HT1080細胞其內質網壓力和20S 蛋白酶體活性變化…………………………………………………41 第五節、 觀察細胞內部型態之變化……………………………………………43 第六節、 細胞訊息傳遞途徑之相關蛋白表現…………………………………43 第七節、 內質網壓力指標IRE1調控的計劃性細胞死亡表現…………………44 第八節、 合併處理三氧化二砷與蛋白酶體抑制劑 (MG-132)對HOS細胞與HT1080細胞的劑量與時間效應……………………………………45 第九節、 腫瘤異體移植活體動物模式…………………………………………46 第七章、 討論……………………………………………………………………47 第八章、 結論與建議…………………………………………………………52 第九章、 參考文獻……………………………………………………………53 圖表…………………………………………………………………………..61

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