白血病 (leukemia) 為骨髓或淋巴母細胞的基因或染色體受到破壞，失去其正常的功能並停止分化，且異常增生，進而使得正常血球功能受到抑制。 病患的年齡、疾病的進程、基因的突變都會影響白血病的預後結果，目前的治療方式以骨髓移植為主，但受限於捐贈者的來源及免疫反應所引起之排斥作用，而化學療法則會引起抗藥性的產生，導致白血病治療的成效不彰，因此找尋有效治療之方式有其醫療價值。 本論文分四部分探討白血病細胞之分子機轉，在研究中使用 Naja nigricollis toxin γ、piceatannol、caffeine、Bungarus multicinctus protease inhibitor-like protein 1 (PILP-1) ，分別就其影響白血病細胞株 U937 及 K562 細胞之死亡及侵犯分子機制，評估此訊息傳遞路徑應用於治療上的可能性。 實驗結果發現 toxin γ 透過 p38 MAPK 磷酸化抑制 Bcl-2 蛋白質表現，進而破壞粒線體功能，產生 ROS 及釋出 cytochrome c ，活化 caspases 最後引發細胞凋亡； Piceatannol 經由 Ca2+/ p38α MAPK 活化 c-Jun 及 ATF-2 調控細胞內 Fas/FasL 的大量表現，以自體分泌的方式啟動 Fas 下游死亡路徑； Caffeine 則誘使細胞內鈣離子濃度增加並誘導ROS 產生，透過抑制 ERK/c-Fos 及活化 p38 MAPK/c-Jun， 進而調控 MMP-2/-9 的表現，降低細胞的侵犯能力； 而 PILP-1 透過 ERK 去活化及 p38 MAPK 磷酸化抑制 ADAM17 的表現，進而改變 Lyn/Akt 細胞存活訊息傳遞路徑，引發細胞死亡。 綜合之，本研究除瞭解白血病細胞存活或侵犯性分子調控機制外，對治療白血病作用標的提供可能發展的方向。

Leukemia is a hematological neoplasm with abnormal genetic mutation or chromosomal translocation in the myeloblast or lymphoblast, and characterized by accumulation of immature cells and malfunction of lymphocytes and myeloid-derived cells. The prognosis of treatment depends on genetic mutation, chromosomal aberration, disease progression and age of patients. Currently, bone marrow transplantation is a useful therapeutic strategy, but the success in therapy is limited by the bone marrow of donors and life-threatening events such as immune repulsion. Although chemotherapy improves leukemia treatment, long-term chemotherapy usually leads to the production of drug-resistant cancer cells. Thus, the development of new modality in overcoming drug-resistant should be beneficial for in leukemia therapy. In this thesis, Naja nigricollis toxin γ, piceatannol, caffeine, and Bungarus multicinctus protease inhibitor-like protein 1 (PILP-1) are employed to investigate the molecular mechanisms in regulating apoptosis and invasion of leukemic cell lines K562 and U937. Hopefully, the signaling pathways elicited by these treatments may be aid in identifying new targets in treating leukemia. Toxin γ inducing cell death is found to evoke p38 MAPK-mediated Bcl-2 down-regulation, which facilitates mitochondria dysfunction, ROS generation and cytiochrome c release. Finally, activation of caspases leads to apoptotic death of toxin γ-treated cells. Piceatannol elicits Ca2+/p38α MAPK- mediated c-Jun and ATF-2 phosphorylation, leading to up-regulation of Fas/FasL protein expression and autocrine Fas-mediated death pathway activation. Caffeine treatment down-regulates MMP-2/-9 down-regulation via Ca2+/ROS-mediated inactivation of ERK/c-Fos and activation of p38 MAPK/c-Jun pathway. Consequently, caffeine treatment suppresses invasion of leukemia cells. PILP-1-induced ADAM17 down-regulation suppresses Lyn-mediated Akt phosphorylation, resulting in death of PILP-1-treated leukemia cells. Taken together, the results of the present study elucidate the signaling pathways responsible for apoptosis and invasion of leukemia cells. Moreover, these findings might suggest new targets in developing therapeutic strategy in treating leukemia.

中文摘要 3
英文摘要 4
縮寫表 6
前言 8
實驗材料 12
實驗方法 16
第一部分： Toxin γ 透過 p38 MAPK 及 ROS 導致白血病細胞凋亡 29
　研究背景 30
　研究動機 32
　實驗結果 33
　討論 39
　圖文說明 41
第二部分： Piceatannol 透過 Ca2+/p38α MAPK 活化 c-Jun 及 ATF-2 促進 Fas/FasL 大量表現引發白血病細胞凋亡之機制 53
　研究背景 54
　研究動機 57
　實驗結果 58
　討論 63　
圖文說明 65
第三部分： Caffeine 透過 Ca2+/ROS 抑制 ERK/c-Fos 以及活化 p38 MAPK/c-Jun 路徑抑制 MMP-2/-9 表現調控細胞之侵犯之能力 79
　研究背景 80
　研究動機 84
　實驗結果 86
　討論 92
　圖文說明 94
第四部分： PILP-1 透過 ADAM17 調控 Lyn/Akt 路徑導致細胞凋亡 106
　研究背景 107
　研究動機 113
　實驗結果 114
　討論 124
　圖文說明 126
總結 149
參考文獻 154
歷年發表著作 187
附錄

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