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研究生:張永羣
研究生(外文):Yong-Qun Chang
論文名稱:植物成分deoxyelephantopin和其衍生物在三陰性乳癌細胞所誘導之活性氧化物和胞外小體分泌之機制
論文名稱(外文):The molecular mechanisms of phytoagent deoxyelephantopin and its derivative induced ROS production and exosome secretion in triple negative breast cancer cells
指導教授:徐麗芬徐麗芬引用關係
指導教授(外文):Lie-Fen Shyur
口試日期:2017-06-21
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生化科技學系
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:2017
畢業學年度:105
語文別:中文
論文頁數:56
中文關鍵詞:乳癌倍半萜內脂活性氧化物胞外小體癌症治療
外文關鍵詞:breast cancersesquiterpene lactonereactive oxygen speciesexosomecancer therapy
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三陰性乳癌 (Triple negative breast cancer, TNBC)與其他乳癌子型態相比是一種術後復原率最差的乳癌子型態。我們先前證明過從地膽草 (Elephantopus scaber)所分離出來的一種倍半萜類化合物deoxyelephantopin (DET) 和它的半有機合成衍生物DETD-35可以有效的抑制人類三陰性乳癌MDA-MB-231的細胞活性。與此同時,我們也發現兩種化合物可以誘導三陰性乳癌生成活性氧化物(reactive oxygen species, ROS)、提升粒線體離子通道的蛋白(voltage-dependent anion channel 1, VDAC1)的表現與增加胞外小體 (exosome)釋放到培養基內。因此我們假設DET和DETD-35所誘導的活性氧化物必定參與胞外小體的釋放或是改變它的活性。本研究的目標為揭發DET和DETD-35對抗三陰性乳癌未知的分子機制,首先發現DET和DETD-35可以破壞粒線體的結構,並且產生胞內空泡與提升胞內鈣離子濃度。而這些影響都可以被活性氧化物的清除者 (N-acetyl-L-cysteine, NAC)的前治療所清除。一般認為胞外小體的釋放機制不是鈣離子依賴就是非鈣離子依賴型。我們先前的研究指出前治療鈣離子的螯合劑 (BAPTA-AM)可以減少DET和DETD-35誘導三陰性乳癌釋放胞外小體,這個結果顯示了DET和DETD-35所誘導的胞外小體釋放機制為鈣離子依賴型。我們使用超高速離心機分離與純化胞外小體並研究它們的潛在功能。有趣的是,兩種化合物所誘導的胞外小體都具有抗三陰性乳癌細胞增生的活性,而且前治療NAC可以回復胞外小體的細胞毒性。這個結果顯示了DET和DETD-35所誘導的活性氧化物可以透過改變胞外小體內的特定蛋白來影響胞外小體的活性。西方墨點法的分析結果顯示出兩種化合物治療可以降低胞外小體內一些與癌症生成和轉移的蛋白表現,例如lysyl oxidase homolog 2 (LOXL2)、EGF-like repeats and discoidin I-like domains 3 (EDIL3)和 milk fat globule-EGF factor 8 protein (MFGE8),而這些影響都可以被NAC的前治療所復原。最後,這個研究提供一個新穎的觀點關於倍半萜類化合物DET和DETD-35透過氧化壓力所調節的胞外小體活性與功能抑制三陰性乳癌的細胞活性。
Triple negative breast cancer (TNBC) is a breast cancer subtype which shows worst postoperative recovery rates among other subtypes. We previously demonstrated that deoxyelephantopin (DET), a sesquiterpene lactone identified from medicinal plant Elephantopus scaber, and its semi-organically synthetically derivative DETD-35 can significantly inhibit a human TNBC cell line MDA-MB-231 activity; meanwhile both compounds were observed to induce reactive oxygen species (ROS) production, elevate voltage-dependent anion channel 1 (VDAC1), a mitochondrial metabolite transporter expression, and increase exosome released from TNBC cells into the cultural media. We thus hypothesized that DET or DETD-35 induced ROS production might be involved or associated with exosomes secretion or their function. The objective of this study was to elucidate the underlying molecular mechanism of DET and DETD-35 against TNBC cells, first observed that DET or DETD-35 induced structural damages in mitochondria, cytoplasmic vacuoles formation and intracellular calcium levels can be reversed by ROS scavenger, N-acetyl-L-cysteine (NAC) pretreatment. Exosomes release mechanisms are known to be either calcium-dependent or calcium-independent. We previously demonstrated that calcium chelator, BAPTA-AM, can blocked the exosome secretion in DET or DETD-35 treated TNBC cells, suggesting a calcium-dependent exosome release mechanism was activation by DET and DETD-35. The secreted exosomes were isolated and purified by ultracentrifugation, and their potential functions were investigated. Intriguingly, both compounds induced exosomes revealed anti-proliferative activity against TNBC cells, and pretreatment with NAC reversed the cytotoxic effect of exosomes. The results suggest that DET and DETD-35 treatment induced ROS production could affect exosome function and that might be through changing specific exosomal proteins expression profile or activity. Immunoblotting analysis showed that down-regulation of the tumorigenesis and metastasis related proteins, such as lysyl oxidase homolog 2 (LOXL2), EGF-like repeats and discoidin I-like domains 3 (EDIL3), and milk fat globule-EGF factor 8 protein (MFGE8) in the exosomes responsive to either compound treatment which were significantly reversed by NAC pretreatment. In summary, this study provide novel mechanistic insight of plant sesquiterpene lactone DET and DETD-35 analog on inhibiting TNBC cell activity through oxidative stress-mediated exosomal activity and function.
口試委員審定書…………………………………………………………………... I
摘要………………………………………………………………………………... II
Abstract………………………………………………………………………......... IV
Table of Contents………………………………………………………………….. VI
List of Figures……………………………………………………………………... VIII
Abbreviations……………………………………………………………………… IX
1. Introduction……………………………………………………………........ 1
1.1 Triple negative breast cancer cell…………………………………………... 1
1.2 Exosomes…………………………………………………………................ 2
1.3 Reactive oxygen species (ROS) and mitochondrial dysfunction…………... 3
1.4 The pharmacological activities of deoxyelephantopin (DET) and its derivative……………………………………………………………………
5
1.5 Objectives and specific aims of this study………………………………..… 7
2. Materials and Methods………………………………………………........... 9
2.1 Cell lines and culture conditions…………………………………………… 9
2.2 Chemicals and reagents……………………………………………….…..... 9
2.3 Isolation and structure elucidation of DET and its derivative DETD-35....... 10
2.4 Isolation and characterization of exosomes derived from MDA-MB-231 cells……………………………………………………………………….…
10
2.5 Cell viability assay………………………………………………………….. 12
2.6 Measurement of intracellular calcium level………………………………... 12
2.7 Determination of ROS level……………………………………………....... 13
2.8 Immunofluorescence cell staining………………………………………...... 13
2.9 Protein extraction…………………………………………………………… 14
2.10 Western blotting………………………………………………….…………. 15
2.11 Statistical analysis…………………………………………………............... 16
3. Results…………………………………………………………………......... 17
3.1 DET and DETD-35 inhibited cell proliferation and changed cell morphology of MDA-MB-231 cells…………………………………….…..
17
3.2 DET and DETD-35 caused mitochondrial dysfunction………………….…. 17
3.3 DET and DETD-35 induced an intracellular calcium level increase in MDA-MB-231 cells…………………………………………………………
18
3.4 DET and DETD-35 significantly induced ROS production in MDA-MB-231 cells but not in MCF10A cells………………………….......
19
3.5 Anti-oxidant NAC reversed DET and DETD-35 induced cytotoxicity and cytosolic calcium level in MDA-MB-231 cells……………………..............
20
3.6 DET and DETD-35 promoted exosome release and changed its activity in MDA-MB-231 cells………………………………………………………....
21
3.7 DET and DETD-35 inhibited exosomes function via ROS production in treated TNBC cells………………………………………………….............
24
4. Discussion………………………………………………………………....... 27
5. Conclusion and Future works…………………………………………......... 32
6. Reference……………………………………………………………….…... 33
7. Appendix……………………………………………………………………. 56
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