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系統識別號 U0026-0601201619354200
論文名稱(中文) 超氧化物歧化酶 (SOD1) 在骨髓性白血病所扮演的角色
論文名稱(英文) The role of superoxide dismutase 1 in myeloid leukemia
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 104
學期 2
出版年 104
研究生(中文) 陳玉霖
研究生(英文) Yu-Lin Chen
學號 S58961565
學位類別 博士
語文別 英文
論文頁數 105頁
口試委員 指導教授-簡偉明
召集委員-呂增宏
口試委員-張明熙
口試委員-黃金鼎
口試委員-洪文俊
口試委員-馬明琪
中文關鍵字 超氧化物歧化酶  超氧化物  蛋白激酶D2  蛋白激酶Cδ  巨核細胞分化  細胞壞死 
英文關鍵字 SOD1  superoxide  PKD2  PKCδ  megakaryocyte differentiation  necrosis 
學科別分類
中文摘要 白血病 (leukemia)為未完全分化癌症的一種,可藉分化療法治療。白血病細胞在受到分化刺激後,亦會引起細胞死亡。另一方面,活性氧化物質 (Reactive oxygen species, ROS) 的代謝影響白血病細胞生長、死亡及分化。其中,超氧化物歧化酶 (Superoxide dismutases, SODs) 是主要的抗氧化酶之一,且在骨髓性白血病 (myeloid leukemia) 細胞中常有較高的表現量。然而,對於超氧化物歧化酶在骨髓性白血病細胞死亡及分化中所扮演的角色仍未有報導。本研究利用佛波酯 (phorbol-12-myristate-13-acetate, PMA) 處理骨髓性白血病細胞株作為研究模型,我們發現佛波酯除了使骨髓性白血病細胞產生類巨核細胞分化外,也伴隨著細胞死亡,同時超氧化物歧化酶-1表現降低,而超氧化物歧化酶-2卻不受影響。超氧化物歧化酶-1抑制劑ATN-224,或shRNA抑制超氧化物歧化酶-1的表達量或其活性,可以增強佛波酯引起之細胞死亡和減少細胞多倍體的產生。相對,超表現超氧化物歧化酶-1能阻止佛波酯的部分作用。再者,敲減蛋白激酶D2 (protein kinase D2, PKD2) 或蛋白激酶Cδ (protein kinase Cδ, PKCδ) 可阻止佛波酯引起之超氧化物歧化酶-1表現量降低 ; 同時亦可增加佛波酯引起之多倍體的增加,而敲減蛋白激酶Cδ則可促進佛波酯引起之巨核細胞表現抗原 (CD41和CD61) 的表現。此外,敲減蛋白激酶D2和蛋白激酶Cδ都可減少骨髓性白血病細胞的血型糖蛋白的基礎表現量。顯示蛋白激酶D2和蛋白激酶Cδ會參與在巨核細胞分化的調控。除此之外,乙酰半胱胺酸 (Acetylcysteine, NAC) 可抑制佛波酯引起之骨髓性白血病細胞死亡,敲減蛋白激酶D和蛋白激酶Cδ亦有相似作用。再者,佛波酯經由活化cathepsin B及促使 poly (ADP-ribose) polymerase (PARP) 的裂解,而引起之細胞壞死。最後,超氧化物歧化酶-1抑制劑ATN-224會抑制骨髓性白血病細胞生長,和促進細胞死亡。此外,ATN-224也會增加Ara-C抑制骨髓性白血病細胞生長的效果。總之,本研究提供了超氧化物歧化酶-1參與在骨髓性白血病細胞死亡和分化的証據,抑制超氧化物歧化酶-1在臨床上治療骨髓性白血病應有助益。
英文摘要 Differentiation-inducing therapy is used to treat patients who have undifferentiated cancer, such as leukemia. During induction stimulation, leukemia cell differentiation is always observed together with cell death. Reactive oxygen species (ROS) metabolism is involved in myeloid leukemia cell proliferation, death and differentiation. Superoxide dismutases (SODs) are major antioxidant enzymes that are highly expressed in myeloid leukemia cells. However, the role of SODs in cell death and differentiation is still largely unknown. In this study, we used phorbol-12-myristate-13-acetate (PMA) to treat myeloid leukemia cell lines for the study. We found that PMA-induced megakaryocytic differentiation in myeloid leukemia cells is accompanied with cell death and SOD1 down-regulation, while SOD2 expression is not affected. Moreover, inhibition or silencing of SODs further increases cell death and decreases polyploidization induced by PMA that could be partially reversed by SOD1 overexpression. Moreover, PMA-attenuated SOD1 expression can be reversed by silencing of protein kinase D2 (PKD2) and protein kinase Cδ (PKCδ). Furthermore, PKD2 inhibited polyploidization and PKCδ suppressed the expression of selective megakaryocyte (MK) surface marker, CD41 and CD61, while both PKD2 and PKCδ silencing reduced the basal level of glycophorin A (GPA) in untreated myeloid leukemia cells. These results indicate that both PKD2 and PKCδ participated in differentiation regulation. N-acetylcysteine (NAC) and silencing of PKD2 or PKCδ also reversed the necrotic death signal, including activation of cathepsin B and cleavage of poly (ADP-ribose) polymerase (PARP) induced by PMA. The role of SOD1 is clarified when ATN-224, a SOD1 specific inhibitor, inhibits cell proliferation and promotes cell death in myeloid leukemia cells without PMA treatment. Finally, ATN-224 enhanced the inhibition of cell proliferation by Ara-C. Taken together, the results demonstrate that SOD1 regulates cell death and differentiation in myeloid leukemia cells. Inhibition of SOD1 by inhibitor such as ATN-224 may be beneficial for myeloid leukemia therapy.
論文目次 中文摘要………………………………………………………………………….i
ABSTRACT……………………………………………………………………….iii
誌謝…………………………………………………………………………………………v
LIST OF FIGURES……………………………………………………………….vii
LIST OF LIST OF ABBREVIATIONS…………………………………………….xi
INTRODUCTION…………………………………………………………………1
MATERIALS AND METHODS…………………………………………………..13
STUDY PURPOSE………………………………………………………………..19
STUDY MODEL…………………………………………………………………..20
RESULTS………………………………………………………………………….21
DISCUSSION………………………………………………………………………33
CONCLUSION…………………………………………………………………….42
REFERENCE………………………………………………………………………43
FIGURES…………………………………………………………………………..54
PUBLICATION…………………………………………………………………………..105
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