臺灣博碩士論文加值系統

三陰性乳癌 (TNBC) 使用一般常用之化療藥物難以治癒，且預後較差。腫瘤壞死因子相關細胞凋亡配體 (TRAIL) 在目前臨床試驗是用於癌症的治療。不幸的是，臨床上病患對TRAIL會產生抵抗性。因此，目前迫切需要找尋能使細胞對TRAIL敏感的藥物。紫檀芪 (pterostilbene, PTER) 屬於白藜蘆醇 (resveratrol) 的天然甲氧基類似物 (methoxylated analogue)，具有多種藥理活性。本研究探討紫檀芪是否能夠影響TRAIL誘導具有TRAIL抵抗性的三陰性乳癌細胞產生細胞凋亡。結果顯示PTER可以誘導具有TRAIL抵抗性的三陰性乳癌BT-20 細胞產生細胞凋亡並能有效增強TRAIL誘導BT-20和MDA-MB-468細胞產生細胞凋亡。進一步探討其機制，證明紫檀芪能減少BT-20 細胞的抗凋亡蛋白質survivin, Bcl-xL 和c-FLIPS/L ，但是不影響Bcl-2；也能使Bid蛋白質被剪切活化並且增強促凋亡蛋白質Bax的表現。紫檀芪能誘導細胞表現死亡受體DR5和DR4、減少BT-20細胞誘導受體DcR2的表現，但不影響DcR1的表現。本研究也證明紫檀芪透過活性氧 (ROS) 引起ERK 1/2和p38蛋白激酶的活化進而誘導DR4和DR5的表現，並且證實活性氧對紫檀芪加強TRAIL誘導細胞凋亡的重要性。總結，我們的研究結果證明，紫檀芪加強TRAIL誘導細胞凋亡可以透過活性氧引起ERK 1/2和p38的活化誘導DR4和DR5的表現、減少抗凋亡蛋白質的表現和增加促凋亡蛋白質的表達。

Triple-negative breast cancer (TNBC) is refractory to commonly used chemotherapeutic agents, as a result it leads to relatively poor prognosis. TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer. Unfortunately, patients develop resistance to the TRAIL, therefore, agents that can sensitize cells to TRAIL are urgently needed. Pterostilbene (PTER), a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities. In the present study, we investigated whether PTER affect TRAIL-induced apoptosis and its mechanism in TRAIL-resistant TNBC cells. First, our results indicated that PTER induced apoptosis in TNBC BT-20 cells. Next, we found that PTER enhanced TRAIL-induced apoptosis in TRAIL-resistant TNBC BT20 and MDA-MB-468 cells. We demonstrated that PTER induced both death receptor 5 (DR5), DR4 and decreased decoy receptor 2 (DcR2) expression. PTER also decreased the expression of anti-apoptotic proteins survivin, Bcl-xL and c-FLIPS/L, but had minimal effect on the expression of Bcl-2. PTER caused the cleavage of bid protein and enhanced the expression of pro-apoptotic Bax. Moreover, we found that PTER induced DR4 and DR5 expression through the reactive oxygen species (ROS) –mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen activated protein kinase (p38 MAPK). Overall, our results show that PTER can potentiate TRAIL-induced apoptosis through the ROS–mediated activation of ERK 1/2 and p38 MAPK leading to DR4 and DR5 induction and down-regulation of anti-apoptotic proteins.

考試委員審定書影本 ............................................................................. I
中文摘要 ......................................................................................II
英文摘要 ..................................................................................... III
誌謝 ........................................................................................ IV
目錄 ......................................................................................... V
圖表目錄 ..................................................................................... IX
附圖 ........................................................................................ IX
附表 ......................................................................................... X
結果圖 ....................................................................................... X
第一章 緒論 ................................................................................... 1
第一節 癌症 (Cancer) .......................................................................... 1
第二節 乳癌 (Breast cancer) ................................................................... 4
第三節 乳癌種類與三陰性乳癌 (Triple negative breast cancer) ...................................... 6
第四節 細胞凋亡 (Apoptosis) .................................................................... 8
一、 細胞凋亡之介紹 ............................................................................. 8
二、 Caspases (Cysteine-aspartic specific protease) ......................................... 10
三、 細胞凋亡之途徑 ............................................................................ 13
(1) 內在路徑 (Intrinsic apoptotic pathway) ................................................... 13
(2) 外在路徑 (Extrinsic apoptotic pathway) ................................................... 14
第五節 TRAIL與TRAIL receptor誘導細胞凋亡之介紹 ................................................... 17
第六節 細胞抵抗TRAIL誘導細胞凋亡之機制 ............................................................ 21
第七節 紫檀芪 (Pterostilbene, PTER) ........................................................... 22
第八節 研究動機 ................................................................................ 24
第二章 材料與方法 .............................................................................. 25
第一節 材料來源 ................................................................................ 25
一、 細胞來源 ................................................................................. 25
二、 實驗藥物來源 .............................................................................. 25
三、 藥品試劑 ................................................................................. 25
四、 抗體 (Antibody) .......................................................................... 27
五、 主要儀器耗材 .............................................................................. 28
第二節 實驗方法 ................................................................................ 30
一、 細胞繼代培養 .............................................................................. 30
二、 細胞冷凍保存 .............................................................................. 30
三、 細胞活化 ................................................................................. 31
四、 細胞存活率分析 (MTT assay) ................................................................ 31
五、 流式細胞儀分析 (Flow cytometry) ........................................................... 32
六、 西方墨點法 (Western blot) ................................................................ 32
(1) 蛋白質萃取 (Protein extraction) ........................................................... 32
(2) 蛋白質定量分析 ............................................................................. 33
(3) 蛋白質之電泳分析 (SDS-PAGE) ................................................................ 34
(4) 轉漬與影像呈現 ............................................................................. 34
七、 細胞群落試驗 (Clonogenic assay) ............................................................ 36
八、 胞內ROS的測定 ............................................................................. 36
九、 統計分析 .................................................................................. 37
第三章 研究結果 ................................................................................ 38
第一節 PTER對TRAIL抵抗性之三陰性乳癌細胞的影響 ..................................................... 38
第二節 PTER增強TRAIL誘導BT-20和MDA-MB-468細胞產生細胞凋亡 .......................................... 43
第三節 PTER影響抗凋亡蛋白質 (anti-apoptotic protein) 和促凋亡蛋白質的表現 (pro-apoptotic protein) .... 48
第四節 PTER影響BT-20細胞表現TRAIL receptor，並探討在其他細胞的作用 ................................... 51
第五節 ROS對PTER誘導BT-20細胞表現DR4、DR5的影響以及對細胞凋亡之影響 .................................... 54
第六節 PTER影響MAPK (mitogen-activated protein kinase) 路徑 ..................................... 57
第七節 MAPKs對PTER誘導DR4、DR5表現的影響 .......................................................... 59
第八節 探討MAPKs與ROS之間的關係 ................................................................... 61
第四章 討論 ..................................................................................... 63
第五章 結論 ..................................................................................... 69
第六章 參考文獻 .................................................................................. 71

圖表目錄
附圖
附圖一、台灣歷年惡性腫瘤死亡率與死亡人數趨勢圖 ......................................................... 3
附圖二、癌細胞轉移 ................................................................................ 3
附圖三、細胞凋亡與細胞壞死之示意圖 ................................................................... 9
附圖四、Caspase之結構 ............................................................................ 11
附圖五、Caspase proenzyme 之結構 ................................................................. 11
附圖六、細胞凋亡的內在路徑和外在路徑 ................................................................. 15
附圖七、細胞凋亡的內在路徑和外在路徑相互連結 ........................................................... 16
附圖八、TRAIL和DR5的立體結構 ...................................................................... 17
附圖九、TRAIL receptor 的結構 .................................................................... 18
附圖十、細胞凋亡的訊息傳遞路徑 ...................................................................... 19
附圖十一、Pro-apoptotic receptor agonists ....................................................... 20
附圖十二、TRAIL-resistant 的機制 ................................................................. 21
附圖十三、 Pterostilbene的化學結構 ................................................................ 23
附圖十四、ROS造成細胞癌化之原因 ..................................................................... 66
附圖十五、Cancer redox biology: a biological basis for therapeutic selectivity.................... 67
附表
附表一、台灣地區100年國人癌症標準化死亡率比較表 ......................................................... 4
附表二、乳癌分期表 ................................................................................. 5
附表三、Caspase 的分類 ............................................................................ 12
結果圖
圖一、PTER對TRAIL抵抗性之三陰性乳癌細胞的影響 ......................................................... 40
圖二、PTER增強TRAIL誘導BT-20和MDA-MD-468細胞產生細胞凋亡 ............................................. 45
圖三、PTER 對BT-20細胞表現抗凋亡蛋白質和促凋亡蛋白質的影響............................................... 49
圖四、PTER影響不同癌細胞表現TRAIL receptor .......................................................... 52
圖五、ROS對PTER誘導BT-20細胞表現DR4、DR5的影響 ....................................................... 55
圖六、PTER對BT-20細胞的MAPK路徑之影響 ............................................................... 58
圖七、MAPK對PTER誘導DR4、DR5表現的影響 .............................................................. 60
圖八、探討MAPKs與ROS之間的關係 ...................................................................... 62
圖九、PTER增強TRAIL誘導細胞凋亡之機制 ................................................................ 70

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