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系統識別號 U0026-1508201306292800
論文名稱(中文) 合併放射線治療及蛋白酶體抑制劑於胰臟癌細胞株之協同毒殺作用
論文名稱(英文) Synergistic cell-killing effects of irradiation and proteasome inhibitor in pancreatic cancer
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 101
學期 2
出版年 102
研究生(中文) 林姝妏
研究生(英文) Shu-Wen Lin
學號 s76991097
學位類別 碩士
語文別 中文
論文頁數 75頁
口試委員 指導教授-王應然
口試委員-潘敏雄
口試委員-郭靜娟
口試委員-何聖佑
中文關鍵字 胰臟癌  蛋白酶體抑制劑  放射線治療  自體吞噬  內質網壓力 
英文關鍵字 Pancreatic cancer  protrasome inhibitor  radiotherapy  autophagy  endoplasmic reticulum stress 
學科別分類
中文摘要 胰臟癌為具有侵略性且高度致死率的一種癌症,胰臟癌雖然只佔全部癌症的3%,但目前其為最困難治療的癌症之一,儘管目前透過手術、放射線與化學藥物來治療胰臟癌,但仍然有超過百分之九十的胰臟癌患者因對於化學藥物的抗性而死亡,因此,仍然需要更有效的治療策略來提高胰臟癌的治癒率。MG132是一種具有可逆性的蛋白酶體抑制劑,其可抑制經由泛蛋白標示的蛋白被蛋白酶體分解,而在許多體外試驗的研究中發現,蛋白酶體抑制劑具備可有效殺死癌細胞的能力,本研究目的主要利用體外試驗與原部位異種移植動物模式,透過合併蛋白酶體抑制劑MG132與放射線的處理,探討是否能有效的抑制胰臟癌生長並進一步深入分析其相關之調控機制。在體外試驗中,分別以蛋白酶體抑制劑MG132、放射線單獨與合併組處理細胞後,以trypan blue 分析其細胞存活率,並利用CalcuSyn軟體計算其combination index (CI);以流式細胞儀分析細胞週期、早期細胞凋亡與酸性小泡的百分比,並以acridine orange染色觀察自體吞噬所形成的酸性小泡(AVO);另以電子顯微鏡觀察細胞的構造變化,並藉由西方墨點法來測定內質網壓力與自體吞噬相關蛋白之表現量變化。在動物實驗中,採用胰臟癌原部位異種移植動物模式,以活體分子影像系統監測腫瘤生長情形,並利用組織切片染色觀察各組胰臟的病理變化,另一方面,利用免疫組織化學染色法分析自體吞噬(LC3)與腫瘤增生(PCNA)指標蛋白的表現量變化。結果顯示,胰臟癌細胞株MiaPaCa-2與PANC-1在合併處理放射線與蛋白酶體抑制劑MG132後抑癌效果皆較單獨處理藥物組別顯著,而合併處理的組別會延長MiaPaCa-2細胞於細胞週期G2/M 期的停滯,且更顯著提高自體吞噬百分比,但早期細胞凋亡百分比與單獨處理組並無太大差異。此外,相較於單獨處理放射線或蛋白酶體抑制劑,在MiaPaCa-2細胞中自體吞噬指標LC3-II與內質網壓力指標IRE1α的表現量有明顯增加的趨勢,而單獨給予蛋白酶體抑制體與合併處理的組別在另一自體吞噬指標p62/SQSTM1的表現量均有增加的情形,並發現訊息傳遞途徑中合併處理的組別其磷酸化的p38與JNK蛋白表現量明顯增加,表示p38與JNK途徑受到活化,同時也發現合併處理放射線合併蛋白酶體抑制劑會透過抑制TAK1-TRAF6 訊息傳遞路徑對 MiaPaCa-2細胞誘發自體吞噬,為了進一步確認合併處理所誘發自體吞噬所扮演的角色,在MiaPaCa-2細胞處理自體吞噬抑制劑3-methyladenine可降低經合併處理所誘發的自體吞噬百分比和細胞毒性,並在合併處理的組別加入抑制autophagosome-lysosome fusion 作用的抑制劑bafilomycin A1,其LC3-II的表現量明顯增加,表示自噬細胞流的確有增加的情況。在人類胰臟癌原部位異種移植動物模式中,合併處理放射線與蛋白酶體抑制劑MG132可有效抑制胰臟腫瘤的生長,且相較單獨處理藥物組別可顯著降低PCNA和TRAF6以及增加LC3的表現量。綜合以上結果可知,合併處理蛋白酶體抑制劑可經由誘發自體吞噬和內質網壓力增加放射線對於胰臟癌細胞之抗癌效果。
英文摘要 Pancreatic cancer is an more aggressive and highly lethal disease. The cancer is one of the most difficult conditions to treat, although it only accounts for 3% of all cancers. Despite advances in surgery, radiotherapy, and chemotherapy, more than 90% of pancreatic cancer patients die of chemoresistance. Therefore, more effective therapies are clearly needed for treatment of this cancer. MG132 is a reversible and cell-permeable proteasome inhibitor that reduces the degradation of ubiquitin-conjugated proteins in cells. Many in vitro studies have demonstrated that proteasome inhibitors kill cancer cells. The purpose of this study was to investigate that proteasome inhibitor MG132 potentiate the antitumor efficacy of irradiation (IR) both in vitro and in an orthotopic mouse model and assess their underlying mechanisms. In the in vitro study, cell viability was screened by trypan blue exclusion assay. The combination index (CI) was analyzed by CalcuSyn softwore. Cell cycle distribution and early apoptosis with Annexin V-FITC apoptosis detection kit were analyzed by flow cytometry. Acidic vesicular organelles (AVOs) was visualized by fluorescence microscopy. Ultrastructure of cells were analyzed by electron microscopy. The endoplasmic reticulum (ER) stress and autophagic-related protein expression were detected western blot analysis. The orthotopic xenograft model was used to investigate the effects of MG132 and IR alone or in combination in vivo and tumor volumes was monitored by the bioluminescence IVIS Imaging System 200. The pathological change was analyzed by Hematoxylin & Eosin Staining (H&E stain). The expression of markers of autophagy (LC3) and proliferation (PCNA) was determined by immunohistochemistry. The results indicated that the anti-cancer effect of combined treatment is more effective than IR or MG132 alone in human pancreatic carcinoma MiaPaCa-2 cells and PANC-1 cells. The combined treatment induced a significantly prolonged G2/M arrest. In addition, combined treatment induced autophagy but not apoptosis in MiaPaCa-2 cells. Furthermore, the expression of LC3-II (an autophagic-related protein) and IRE1α (a ER stress-related protein) were increased in combination of IR and MG132 in MiaPaCa-2 cells, and the expression of p62/SQSTM1 was increased in MG132 alone or combined treatment. Moreover, combined treatment significantly increased phosphorylation of the p38 and JNK in MiaPaCa-2 cells. We also found that the combination of IR and MG132 inhibited the expression of TAK1 and TRAF6 in MiaPaCa-2 cells as well as triggering autophagy. To further confirm the role of autophagy in combined treatment-induced cell death, we pretreated of 3-methyladenine in MG132 and IR-co-administrated MiaPaCa-2 cells, and found that autophagy and cell death were a significantly decreased. Then we used bafilomycin A1, an inhibitor of autophagosome-lysosome fusion, to inhibit the autophagy flux. The results showed that the LC3-II levels in MG132 and IR-co-administrated cells treated with combined treatment were significantly elevated by bafilomycin A1. In an orthotopic model of human pancreatic cancer, we found that the combined treatment group significantly suppressed the growth of the tumor compared to IR-,MG132-alone of vehicle control mice. In addition, The expression of PCNA and TRAF6 were significantly decreased, and LC3 was increased in the combination of IR and MG132 compared with IR or MG132 alone in the orthotopic tumor samples. Taken together, these results demonstrated that combined treatment of MG132 and IR increased the therapeutic efficacy of pancreatic carcinoma through the induction of autophagy and ER stress.
論文目次 第一章、序論 1
第二章、文獻回顧 2
第一節、胰臟癌(Pancreatic cancer)與其治療方式 2
第二節、放射線治療(Radiation therapy)合併化學藥物 4
第三節、蛋白酶體抑制劑(Proteasome inhibitor) 5
第四節、內質網壓力 (Endoplasmic reticulum (ER) stress) 9
第五節、細胞凋亡 (Apoptosis)與自體吞噬 (Autophagy) 10
第六節、原部位異種移植動物模式 (Orthotopic xenografts In vivo model) 13
第三章、研究目的 15
第四章、研究材料與方法 16
第一節、研究材料 16
第二節、研究方法與實驗步驟 23
一、細胞培養(Cell culture) 23
二、細胞解凍 23
三、細胞冷凍 24
四、細胞存活率 (Cell viability) 24
五、協同效應分析(Synergistic interaction) 24
六、細胞週期分析(Cell cycle distribution) 24
七、早期細胞凋亡(Early apoptosis)分析 25
八、自體吞噬(Autophagy)分析 25
九、螢光染色 (Acridine orange) 25
十、穿透式電子顯微鏡 26
十一、細胞群落分析(Clonogenic assay) 26
十二、西方墨點法(Western blotting) 27
十三、干擾性核糖核酸( RNA i) 28
十四、Stable transfection (luciferase) 29
十五、胰臟癌原部位異種移植動物模式(Orthotopic xenografts In vivo model) 29
十六、蘇木紫伊紅染色 (Hematoxylin & Eosin Staining) 31
十七、免疫組織染色(Immunohistochemistry) 31
十八、統計分析 32
第五章、研究架構 33
In Vitro Study 33
In Vivo Study 34
第六章、實驗結果 35
第一節、放射線和蛋白酶體抑制劑MG132對MiaPaCa-2與PANC-1細胞的劑量與時間效應 35
第二節、放射線合併蛋白酶體抑制劑MG132對MiaPaCa-2與PANC-1細胞之毒性效果 35
第三節、放射線合併蛋白酶體抑制劑對MiaPaCa-2細胞株之細胞週期影響 36
第四節、分析合併處理放射線合併蛋白酶體抑制劑MG132對MiaPaCa-2細胞影響細胞凋亡與自體吞噬的變化 37
第五節、探討合併處理放射線合併蛋白酶體抑制劑MG132對MiaPaCa-2細胞誘發自體吞噬的現象 38
第六節、觀察細胞內部形態的變化 39
第七節、探討合併處理放射線合併蛋白酶體抑制劑對MiaPaCa-2細胞誘發內質網壓力現象與細胞訊息傳遞途徑之相關蛋白表現 39
第八節、合併處理放射線合併蛋白酶體抑制劑透過抑制TAK1-TRAF6 訊息傳遞路徑對 MiaPaCa-2細胞誘發細胞計畫性死亡 40
第九節、胰臟癌原部位異種移植動物模式 41
第七章、討論 43
第八章、結論及建議 48
第九章、參考文獻 49
圖表 57
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