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研究生:宋佩玲
研究生(外文):SUNG, PEI LING
論文名稱:新穎蛋白質雙硫鍵異構酶抑制劑抗多形性神經膠質母細胞瘤生長之研究
論文名稱(外文):Study of a novel protein disulfide isomerase inhibitor on the anti-proliferative activity in human glioblastoma multiforme cells
指導教授:梁有志梁有志引用關係
指導教授(外文):LIANG, YU-CHIH
口試委員:葉添順黃偉展梁有志
口試委員(外文):YEH, TIEN-SHUNHUANG, WEI JANLIANG, YU-CHIH
口試日期:2021-07-16
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學檢驗暨生物技術學系碩士班
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2021
畢業學年度:109
語文別:中文
論文頁數:67
中文關鍵詞:蛋白質雙硫鍵異構酶
外文關鍵詞:protein disulfide isomerase
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根據2020年美國腦瘤病例登錄中心(CBTRUS)資料顯示,多型性膠質母細胞瘤屬於中樞神經系統中最常見之惡性腫瘤,但是只有5.5%的患者在診斷後存活超過5年。在臺灣,衛生福利部107年癌症登記的資料統計顯示,腦瘤發生率排名於癌症的第19位。文獻指出,蛋白質雙硫鍵異構酶在各種癌症中高度表現,且會促進癌症發展。當蛋白質雙硫鍵異構酶被抑制時,蛋白質無法合成,會導致未折疊及錯誤折疊蛋白質累積而觸發內質網壓力(endoplasmic reticulum stress, ER stress)和未折疊蛋白質反應(unfolded protein response, UPR)。過多的未折疊蛋白質和失衡的內質網壓力會使細胞週期阻滯及細胞死亡。本篇研究中使用黃偉展教授合成的一系列PACMA31蛋白質雙硫鍵異構酶抑制劑之衍生物,探討其抗多型性神經膠質母細胞瘤生長之分子機轉。首先,使用MTT assay分析PACMA31對於腦癌細胞之存活率,不論是在GBM8401和U87,IC50大約為15 µM。接著,利用MTT assay分析21種PACMA31之衍生物對於腦癌細胞之存活率,經處理48小時結果發現,其中10種化合物具有抑制人類多型性膠質母細胞瘤之細胞株GBM8401和U87存活率之效果。接者將10種化合物,經處理24小時結果發現,No.8不論是在GBM8401和U87其抑制細胞存活率效果最好,IC50大約為30 nM。而後本研究僅選擇No.8衍生物探討其抗腫瘤生長之分子機轉。利用流式細胞儀分析,發現GBM8401及U87 隨著No.8濃度的提升而增加Sub G1的比率。使用西方墨點法分析,發現GBM8401及U87細胞中加入No.8,會增加未折疊蛋白質反應(UPR)的表現,包括 Phospho-PERK, Phospho-eIF2α, GRP78及CHOP;而後也分析細胞凋亡(apoptosis)蛋白質的表現,發現GBM8401及U87細胞中加入No.8,會增加caspase-3, 8, 9及PARP蛋白質表現。為了進一步證實細胞存活率降低是否與細胞凋亡有關,本研究使用了 caspase 3, 8, 9 呈色測定試劑,結果發現 GBM8401 及 U87 細胞中 caspase 3 和 caspase 8 活性增加。另外,使用z-VAD-fmk,caspase抑制劑處理後,細胞存活率會增加,結果說明No.8引起腦癌細胞死亡的主要路徑是活化細胞凋亡。有趣的是,研究發現GBM8401及U87細胞中加入No.8會增加自噬作用標的蛋白質LC3B-II的表現。總結以上的結果,推測No.8可以經由活化內質網壓力、細胞凋亡及自噬作用,進而抑制多型性膠質母細胞瘤的生長。

According to the data from the Central Brain Tumor Registry of the United States in 2020, glioblastoma multiforme (GBM) is the most malignant brain tumor in the central nervous system (CNS). Nevertheless, only 5.5% of GBM patients can survive more than 5 years after diagnosis. In Taiwan, the report on cancer registration from the Ministry of Health and Welfare in 2018 showed that the incidence of primary brain tumors ranked 19th in cancer. Previous studies had found that protein disulfide isomerases (PDI) are highly expressed in various cancers and promoted cancer progression. Inhibition of PDI increased the accumulation of unfolded proteins and misfolded proteins, which induce the unfolded protein response (URP) and endoplasmic reticulum stress. Unfolded proteins overload and ER stress persistent cause cell cycle arrest and even cell death. PACMA31 is known as a protein disulfide isomerase inhibitor and a series of its derivatives have been synthesized by Professor Huang's laboratory. In this study, we chose these derivatives to examine their antitumor activity and the underlying molecular mechanisms. First, we screened the anti-proliferative activity of PACMA31 by MTT assay. The results showed that anti-proliferative activity with IC50 about 15 µM on these two GBM cells. Then, we screened the anti-proliferative activity of 21 PACMA31 derivatives by MTT assay. The results showed that 10 of the derivatives have better inhibitory activity with IC50 < 50 nM in both human glioblastoma multiforme cell lines-GBM8401 and U87. It was found that the No. 8 derivative has the best anti-proliferative activity with IC50 about 30 nM on these two GBM cells. Therefore, we only chose the No.8 derivative to examine its antitumor activity in the study. The flow cytometry analysis showed that No.8 significantly increased SubG1 population in GBM8401 and U87 cells. Using western blot analysis, we found that No.8 increased the expression of unfolded protein response-related proteins, including phosphorylated PERK, phosphorylated-eIF2α, GRP78 and CHOP. Moreover, No.8 treatment also induced the cleaved caspase -3, 8, 9 and PARP, which are usually cleaved during apoptosis. Next, we used caspase 3、8、9 colorimetric assays kit found that caspase 3 and caspase 8 activities were increased in GBM8401 and U87. Finally, we found that pretreatment with z-VAD-fmk increased the cell viability. These results indicate that cell apoptosis is the main pathway for the cell death caused by No.8 treatment. Interestingly, LC3B-II, a reliable marker of autophagosomes was increased in No.8-treated GBM8401 and U87 cells. Overall, these results suggest that the anti-proliferation activity of No.8 might be associated with ER stress, apoptosis, and autophagy in human glioblastoma multiforme cells.
摘要 IV
Abstract V
第壹章 緒論(Introduction) 1
一、 腦癌(Brain cancer) 1
(一)、 腦癌之分類(Classification of Brain cancer) 2
(二)、 腦癌之等級(Grading of Brain cancer) 3
(三)、 腦癌之流行病學(Epidemiology of Brain cancer) 4
(四)、 腦癌之危險因子(Risk factors of Brain cancer) 4
二、 蛋白質雙硫鍵異構酶(Protein disulfide isomerase, PDI) 5
(一)、 蛋白質雙硫鍵異構酶結構(Structure of Protein disulfide isomerase) 5
(二)、 蛋白質雙硫鍵異構酶之功能(Function of Protein disulfide isomerase) 6
(三)、 蛋白質雙硫鍵異構酶家族(Protein disulfide isomerase family) 6
(四)、 蛋白質雙硫鍵異構酶與癌症(Protein disulfide isomerase in cancer) 7
三、 蛋白質雙硫鍵異構酶抑制劑(Protein disulfide isomerase inhibitor) 8
四、 未折疊蛋白反應(Unfolded protein response, UPR) 8
五、 細胞凋亡路徑(Apoptosis pathway) 9
六、 自噬作用(Autophagy) 10
七、 研究動機(Research motivation) 13
第貳章 材料與方法(Materials and Methods) 14
一、 材料(Materials) 14
(一)、 細胞株(Cell line) 14
(二)、 抗體(Antibody) 14
(三)、 化合物(Compounds) 15
(四)、 化學藥品(Chemicals) 15
二、 方法(Methods) 16
(一)、 細胞存活試驗(MTT assay) 16
(二)、 流式細胞儀(Flow cytometry) 16
(三)、 西方墨點法(Western blot assay) 17
(四)、 Caspase 活性測試 (Caspase activity assay) 19
(五)、 Caspase抑制劑試驗(Caspase inhibitor assay) 19
(六)、 統計分析(Statistical analysis) 19
第參章 結果(Results) 20
一、 篩選PACMA31對於腦癌細胞之存活率 20
二、 篩選21種PACMA31之衍生物對於腦癌細胞之存活率 20
三、 篩選10種PACMA31之衍生物對於腦癌細胞之存活率 20
四、 No.8抑制腦癌細胞存活率之機制會增加細胞週期的Sub G1期 21
五、 No.8抑制腦癌細胞存活率之機制與內質網壓力路徑相關 21
六、 No.8抑制腦癌細胞存活率之機制與細胞凋亡路徑相關 23
七、 No.8抑制腦癌細胞存活率之機制與活化自噬作用相關 24
第肆章 討論(Discussion) 25
一、 內質網壓力誘導之未折疊蛋白反應與癌症相關性 25
二、 蛋白質雙硫鍵異構酶成員間的結構差異 26
三、 蛋白質雙硫鍵異構酶抑制劑濃度及機質探討 27
四、 蛋白質雙硫鍵異構酶抑制劑之體內試驗 28
第伍章 參考文獻(Reference) 30
第陸章 目次圖表(Figure list) 37
Figure 1. Effects of PACMA31 on the cell viability of human glioblastoma cells. 38
Figure 2. Effects of PACMA31 derivatives on the cell viability of human glioblastoma cells. 41
Figure 3. Effects of PACMA31 derivatives on the cell viability of human glioblastoma cells. 42
Figure 4. Effects of No.8 on the cell cycle progression in human glioblastoma cells. 47
Figure 5. Effects of No.8 on the endoplasmic reticulum stress marker protein expressions in human glioblastoma cells. 53
Figure 6. Effects of 8-43041B on the apoptotic marker protein expressions in human glioblastoma cells. 56
Figure 7. Effects of 8-43041B on the autophagy marker protein expressions in human glioblastoma cells. 57
第柒章 附錄(Appendix) 58


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