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研究生:鄧妤青
研究生(外文):DENG, YU-CING
論文名稱:蜂膠素C 對人類三陰性乳癌細胞抗腫瘤效應及機制之探討
論文名稱(外文):The anti-tumor effects of propolin C on the human triple-negative breast cancer cells
指導教授:翁孟仕
指導教授(外文):Weng, Meng-Shih
口試委員:簡銘賢華國泰
口試委員(外文):Chien, Ming-HsienHua, Kuo-Tai
口試日期:2016-07-20
學位類別:碩士
校院名稱:輔仁大學
系所名稱:營養科學系碩士班
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:91
中文關鍵詞:乳癌蜂膠素C自噬作用
外文關鍵詞:Breast cancerpropolin Cautophagy
相關次數:
  • 被引用被引用:3
  • 點閱點閱:320
  • 評分評分:
  • 下載下載:55
  • 收藏至我的研究室書目清單書目收藏:1
乳癌列居台灣癌症死亡率第四名,其中三陰性乳癌類型的預後效果較其他類型的乳癌差。蜂膠素C是從台灣蜂膠中識別出具有效的抗腫瘤、抗病毒等作用。然而目前台灣蜂膠素C對乳癌的抗腫瘤作用尚不清楚。故本研究欲探討蜂膠素C對三陰性乳癌細胞抗增生的作用及相關機轉。蜂膠素C抑制一系列的乳癌細胞株生長且不影響人類正常乳腺上皮細胞。三陰性乳癌細胞MDA-MB231於 72小時之IC50 (The inhibitory concentration to afford 50% cell viability)為7.60 ±1.03 。在細胞群形成試驗(Colony formation assay)中,給予蜂膠素C處理下,會隨著劑量增加而抑制細胞群生長。此外,蜂膠素C雖然無法停滯細胞週期,但能誘導自噬作用的標的蛋白(Atg-7、LC3、Beclin-1、p62)表現增加。然而,在給予細胞凋亡抑制劑(Z-VAD(OMe)-FMK)、自噬作用抑制劑(3-Methyladenine及Chloroquine)無法回復蜂膠素C所造成的細胞死亡。此外,蜂膠塑C誘導MDA-MB231的空泡死亡既沒有在DAPI染色中具顯著細胞核的型態變化,也沒有在AO染色具明顯的酸性囊狀胞器現象。給予蛋白合成抑制劑Cycloheximide (CHX)與蜂膠素C共同作用下,LC3和泛素化蛋白會受到抑制,故推測其可能與內質網壓力有關。根據以上結果,蜂膠素C的抗癌作用會透過非細胞凋亡與非自噬作用路徑調節三陰性乳癌細胞死亡。
Breast cancer is the fourth leading cause of cancer death among all cancers. The prognosis of triple negative breast cancer (TNBC) is worse than other types of breast cancer. Propolin C was isolated from Taiwanese propolis which has been demonstrated to possess anti-tumor and anti-viral activity. However, the anti-tumor effect of propolin C on breast cancer is still unclear. The aim of our study was to investigate the anti-tumor effects of propolin C on the human triple negative breast cancer cells. Our results showed that propolin C inhibited a serial of breast cancer cell lines growth rather than normal human mammary epidermal cell. The IC50 (The inhibitory concentration to afford 50% cell viability) of 72 hour was 7.60 ± 1.03 μM in the TNBC (MDA-MB231). The number of surviving colonies was significantly reduced by propolin C in a dose-dependent manner in the clonogenic assay. In addition, propolin C could’t induce cell cycle arrest, but it induced autophagic marker protein (Atg-7, LC3, Beclin-1 and p62) increased. However, propolin C-induced vacuolation was not reversed by apoptosis inhibitor (Z-VAD(OMe)-FMK) or autophagic-related inhibitors (3-methyladenine and chloroquine). In addition, treatment of propolin C induced extensive cytoplasmic vacuolation with neither nuclear changes in the DAPI stain, nor the formation of acidic vesicular organelles in the acridine orange (AO) stain. Treatment of propolin C with cycloheximide (CHX) inhibited LC3 and ubquitinated protein expression. Thus, this phenomenon might be involved with endoplasmic reticulum stress. According to our results, the anti-cancer activity of propolin C was through non-autophagic and non-apoptosis cell death in TNBC.
目錄
謝誌 ……….…………………………………………………………….i
摘要 ……………………………………………………………………iii
Abstract…………………………………………………………………. v
縮寫表…………………………………………………………………... vi
壹、 前言……………………………………………………………….. 1
貳、 文獻回顧 2
一、乳癌定義與類型 2
I. 管腔型(Luminal)乳癌 3
II. 第二型人類上皮生長因子受器(human epidermal growth factor receptor-2, HER-2) 過度表現型乳癌 3
III. 三陰性(Triple negative )乳癌 3
二、乳癌的風險因子與治療方式 4
I. 雌激素受器陽性乳癌(Estrogen receptor positive; ER positive) 5
II. ER陽性乳癌發展與ER 5
III. 雌激素受器信號路徑與抗激素療法 6
三、自噬作用(Autophagy)與乳癌的調節 7
I. 自噬作用機制 7
II. 自噬作用調節 9
四、 乳癌與凋亡分子信號路徑 12
五、 內質網壓力(endoplasmic reticulum stress)與乳癌的調節 13
六、 台灣蜂膠(Taiwanese propolis) 16
I. 蜂膠 16
II. 蜂膠的成分與特性 17
III. 蜂膠的抗癌作用 17
IV. 台灣蜂膠的特性 18
V. 台灣蜂膠的生理特性 19
參、 試驗目的與設計 23
一、 試驗目的 23
二、 實驗設計 23
肆、 實驗材料與方法 26
一、 台灣蜂膠萃取物蜂膠素C 26
二、 實驗材料 26
I. 細胞株 26
II. 培養基 26
III. 藥品試劑 26
IV. 實驗儀器 29
V. 實驗耗材 30
VI. 常用溶液配製 31
VII. 實驗方法 34
伍、 統計分析 40
陸、 實驗結果 41
一、 蜂膠素C對人類乳癌細胞存活率影響 41
二、 蜂膠素C誘導三陰性人類乳癌細胞MDA-MB-231型態變化的影響 42
三、 蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞群形成的影響 43
四、 蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞週期的影響 43
五、 蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞之自噬作用標的蛋白表現 44
六、 蜂膠素 C對人類三陰性乳癌細胞MDA-MB-231細胞生存率之凋亡抑制劑介入下的抑制效果 44
七、 蜂膠素C透過蛋白質轉譯抑制劑影響自噬作用標記蛋白表現 45
柒、 討論……………………………………………………………… 47
一、 蜂膠素C對細胞的毒性作用 47
二、 蜂膠萃取物對細胞週期的影響 48
三、 細胞空泡化形成與影響 49
四、 自噬作用相關蛋白的影響與討論 49
五、 天然化合物與抑制劑共同處理下的作用 50
六、 蛋白泛素化與自噬作用、內質網壓力的關係 51
捌、 結論……………………………………………………………… 53
玖、圖表………………………….......................................................... 55
壹拾、 參考文獻 70
壹拾壹、 附表 88
壹拾貳、 附圖 91


圖目錄
圖 1、蜂膠素C對人類正常乳線上皮細胞MCF-10A存活率的影響… 55
圖 2、蜂膠素C對管腔A型乳癌細胞存活率的影響 56
圖 3、蜂膠素C對管腔B型乳癌細胞存活率的影響 57
圖 4、蜂膠素C對HER-2表現型乳癌細胞存活率的影響 58
圖 5、蜂膠素C對三陰性乳癌細胞存活率的影響 59
圖 6、蜂膠素C對三陰性人壘乳癌細胞MDA-MB-231型態變化的影響 61
圖 7、蜂膠素C對人類三陰性乳癌細胞MDA-MB-231 colony形成的影響 62
圖 8、蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞週期的影響 63
圖 9、蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞生存率之凋亡抑制劑介入下的抑制效果 64
圖 10、蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞之自噬作用標的蛋白表現 65
圖 11、蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞之自噬作用標的蛋白表現 66
圖 12、蜂膠素C對人類三陰性乳癌細胞MDA-MB-231細胞生存率之自噬作用抑制劑介入下的抑制效果 67
圖 13、蜂膠素 C誘導人類三陰性乳癌細胞MDA-MB-231細胞非凋亡與非自噬細胞空泡化死亡 68
圖 14、蜂膠素C透過蛋白質轉譯抑制劑影響自噬作用標記蛋白表現 69
附表目錄
附表 1、乳癌細胞的分子類別 88
附表 2、蜂膠的所有種類、來源以及特色 89
附表 3、台灣蜂膠萃取物不同產季與產量 90
附表 4、台灣蜂膠萃取物對不同革蘭氏菌的抑制作用 90
附圖目錄
附圖 1、台灣蜂膠萃取物蜂膠素A-H 91


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