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研究生:馮柏霖
研究生(外文):Bo-Lin Feng
論文名稱:闡述抗癌藥物Undecylprodigiosin引起細胞凋亡之作用模式
論文名稱(外文):Elucidation of the Modes of Action Underlying the Apoptosis Induced by the Anticancer Drug Undecylprodigiosin
指導教授:張嘉哲張嘉哲引用關係
指導教授(外文):Chia-Che Chang
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
畢業學年度:97
語文別:中文
論文頁數:72
中文關鍵詞:細胞凋亡
外文關鍵詞:apoptosis
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Undecylprodigiosin (UP)屬於一群結構上具有三個砒咯環的天然紅色化合物,可由鏈黴菌屬 (Streptomyces)及鋸桿菌屬 (Serratia)這類微生物代謝生成。本實驗室於 2007年在 TAAP上發表了 UP對人類乳癌細胞株具有選擇性的抑癌效果,是第一篇報導 UP處理下能選擇性地有效引起癌細胞走向凋亡,又不影響良性細胞株生長的研究,但 UP如何引起癌細胞走向凋亡的確切路徑還未被研究。本研究即主要探討 UP引起細胞凋亡之分子機制。結果顯示,UP刺激下死亡受體 (DR4、DR5)表現量明顯增加,而在分離粒線體與細胞質蛋白實驗中,發現 UP處理下粒線體蛋白 cytochrome c與 Smac被大量釋放至細胞質。另外,也觀察到誘導性及作用型caspase (caspase-8, -9, -3)活性隨著 UP劑量的增加而增加,顯示UP刺激下可能同時活化細胞外在 (死亡受體)與內在 (粒線體)凋亡路徑。Caspase抑制劑實驗中,預處理 z-VAD.fmk (廣泛性 caspase抑制劑)及 z-DEVD.fmk (caspase-3抑制劑)均可有效阻斷細胞走向凋亡,顯示 UP引起的凋亡效應依賴 caspase之活性,然而當預處理 z-IETD.fmk (caspase-8抑制劑)或 z-LEHD.fmk (caspase-9抑制劑)則無法有效抑制 UP引起的凋亡效應。接著,我們進一步觀察到 UP刺激下 MAP kinases (JNK、p38、ERK)均有被磷酸化的現象。預處理 MAP kinases抑制劑 (SP600125 (JNK抑制劑)、SB203580 (p38抑制劑)、U0126 (EMK/ERK抑制劑) )後再處理 UP實驗中發現,抑制 JNK及 ERK活性幾乎可以完全阻斷 UP引起的凋亡效應以及 caspase活性。綜合以上結果,證明由 UP引起無論是外生或內生性的凋亡效應均需依賴 caspase活性,且 JNK及 ERK的活化與否決定了 UP活化 caspase之能力。
Undecylprodigiosin (UP), a bacterial metabolite belonging to a family of tripyrrole red pigments produced by microorganisms including Streptomyces and Serratia strains. Previously, our laboratory has validated the anticancer effects of UP in human breast cancer cells. However, the mechanism underlying UP-induced apoptosis is still unclear. In this study, we demonstrated that UP activates both death receptor- and mitochondria-dependent cell death. In the death receptor pathway, treatment with UP substantially up-regulates caspase8 activity accompanied with increase of the levels of DR4 and DR5. In the mitochondrial pathway, cells treated UP led to the mitochondrial release of cytocrome c and Smac to the cytoplasm and the activation of caspase 9. Caspase activity is required for UP-induced apoptosis, as demonstrated by the dramatic blockade of apoptosis by pan-casapse inhibitor z-VAD-FMK and caspase 3 inhibitor z-DEVD-FMK. However, z-IETD-FMK (caspase 8 inhibitor) and z-LEHD-FMK (caspase 9 inhibitor) seem no effect on UP-induced apoptosis. Additionally, we found that UP effectively modulates MAP kinase signaling pathways. In particular, UP-induced apoptosis is abolished in cells pretreated with SP600125 (JNK inhibitor) and U0126 (ERK inhibitor), indicating that UP’s pro-apoptotic effect is mediated by both JNK- and ERK-mediated signaling pathways. Taken together, our results clearly established that UP-induced apoptosis is in a caspase-dependent manner and requires activation of both JNK- and ERK-mediated apoptotic signals.
目次
縮寫字對照表 I
中文摘要 III
Abstract IV
壹、 序論 1
一、 癌症的發生 1
二、 細胞凋亡 (apoptosis) 3
三、 IAP家族蛋白 (The IAP family) 6
四、 Survivin蛋白 7
五、 MAPKs家族蛋白 8
六、 Prodiginine藥物發展史 12
七、 Prodiginine藥物作用模式 15
貳、 研究目的與策略 18
參、 實驗方法 20
一、 細胞培養 20
二、 細胞之長期冷凍保存與解凍 20
三、 藥物處理 21
四、 細胞存活測驗 (cell viability assay) 21
五、 總蛋白萃取(total lysate extraction) 22
六、 蛋白濃度定量分析 (protein quantification): 23
七、 西方墨點法 (western blot): 23
八、 細胞總量 RNA萃取 (total RNA extraction) 26
九、 即時定量 RT-PCR(real time RT-PCR): 27
十、 流式細胞儀分析 28
十一、 Caspase活性分析 30
十二、 粒線體蛋白分離萃取 31
十三、 轉型作用 (transformation) 32
1. 勝任菌體(Competent Bacterial Cell)製備 33
2. 轉型作用(Transformation) 33
肆、 試劑配方 34
Western blot 蛋白質分析藥劑配置: 34
蛋白質萃取藥劑配置: 34
核酸操作藥劑配製: 34
抗體(antibodies): 35
伍、 結果 37
一、 Undecylprodigiosin有效誘導乳癌、直腸癌細胞株之凋亡活性 37
二、 Undecylprodigiosin處理明顯提高 caspase活性 37
三、 Undecylprodigiosin誘導細胞凋亡需要caspase參與 38
四、 Undecylprodigiosin處理提高死亡受器之表現量 39
五、 UP處理誘導粒線體內cytochrome c及 Smac釋放至細胞質 40
六、 Undecylprodigiosin處理下MAP kinase磷酸化之時間效應 40
七、 Undecylprodigiosin誘導細胞凋亡與 MAP kinase磷酸化活化 41
八、 MAP kinase磷酸化影響UP調控caspase活性能力 42
九、 探討survivin與 SP600125抑制UP引起細胞凋亡之關係 43
陸、 討論 44
一、 探討Undecylprodigiosin之抗癌潛力 44
二、 探討Undecylprodigiosin凋亡效應與 caspase活性之關係 45
三、 探討 Undecylprodigiosin誘導 MAP kinase磷酸化之機制 46
四、 推論 SP600125誘導 survivin蛋白大量表現之機制與影響 46
實驗結果圖表 48
參考文獻 66
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