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研究生:陳顧中
研究生(外文):Ku-chung Chen
論文名稱:台灣眼鏡蛇磷脂酶對細胞毒殺分子機制之探討
論文名稱(外文):Cytotoxic mechanisms of Taiwan cobra phospholipase A2
指導教授:張榮賢
指導教授(外文):Long-sen Chang
學位類別:博士
校院名稱:國立中山大學
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
論文出版年:2009
畢業學年度:98
語文別:中文
論文頁數:174
中文關鍵詞:蛇毒
外文關鍵詞:arachidonic acidPLA2phospholipase A2FasLFasJNKROSCap38 MAPKSK-N-SHlysophosphatidylcholineK562
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磷脂酶 A2 (phospholipase A2; PLA2) 為一在鈣離子存在下會水解1,2-diacyl-3-sn-phosphoglycerides 之 2-acyl ester bond 的酵素,且釋放出之產物 fatty acids 及 lysophospholipids 為調控許多生理功能如脂質代謝、細胞分泌及發炎反應等訊息分子之前驅物。 因此 PLA2 不僅在維持正常生理功能上扮演重要的角色,也參與許多發炎相關疾病。 然而其導致細胞死亡的機制仍未釐清。 本研究主旨主要為利用 Naja naja atra PLA2 來處理人類神經母細胞瘤細胞 SK-N-SH 及血癌細胞 K562,並探討 PLA2 誘導細胞死亡的訊息傳遞路徑。 經 PLA2 處理 SK-N-SH 及 K562 細胞後,可觀察到 p38 mitogen-activated protein kinase (p38 MAPK) 或 c-Jun N-terminal kinase (JNK) 活化、extracellularsignal-regulated protein kinase (ERK) 去磷酸化、reactive oxygen species (ROS) 產生、[Ca2+]i 濃度增加、粒線體膜電位喪失 (ΔΨm)、 cytochrome c釋放及 Fas/FasL 蛋白質表現等現象。 分別處理 N-Acetylcysteine (ROS 清除劑)、BAPTA-AM (Ca2+ 螯和劑)、SB202190 (p38 MAPK 抑制劑) 或 SP600125 (JNK 抑制劑) 則可抑制 p38 MAPK 或 JNK 活化並回復細胞生存率、ΔΨm 喪失、 cytochrome c 釋放及抑制 Fas/FasL 蛋白質表現等現象,也促使 ERK 回復磷酸化。 ERK 的活化可減緩 p38 MAPK 所調節 Fas/FasL 表現的效應。 此外,SB202190 及 PLA2共同處理K562 細胞後,可觀察到 p38 MAPK 活性的下降進而造成 JNK 持續活化來促使細胞死亡。 而利用 siRNA 等技術則發現在 K562 細胞中 PLA2 藉由活化 p38 MAPK/ATF-2 或 JNK1/c-Jun 等路徑來調控 Fas/FasL 基因表現。 此外,無酵素活性之 PLA2 處理細胞後仍可造成 Fas/FasL 蛋白質表現及細胞死亡。
利用 PLA2 的水解產物 arachidonic acid (AA) 及 lysophosphatidylcholine (LPC) 處理上述兩種細胞後並不引發 Fas/FasL 蛋白質表現。 並由結果得知 AA 誘導 ROS 及 [Ca2+]i 濃度上升來活化 p38 MAPK/JNK,並藉此破壞粒線體正常運作而導致細胞死亡。 此外,額外使用 U0126 來抑制 ERK 活化則有增進 AA 調控 Fas/FasL 蛋白質表現的能力。 綜合上述結果確認 PLA2 可藉由 [Ca2+]i 及 ROS 來活化 p38 MAPK 或 JNK 並誘導 Fas/FasL 蛋白質表現來部份參與細胞死亡機制。
The enzyme phospholipase A2 (PLA2) specifically hydrolyzes the 2-acyl ester bond of 1,2-diacyl-3-sn-phosphoglycerides releasing fatty acids and lysophospholipids in the presence of Ca2+. Both products represent precursors for signaling molecules that can exert a multitude of biological functions including phospholipid metabolism, exocytosis and inflammation. Consequently, PLA2 not only plays a role in regulating physiological processes, but also exhibits pharmacological effects in inflammatory diseases. Nevertheless, the signaling pathway leading to cell death still remains elusive. In the present study, the cytotoxicity of Naja naja atra PLA2 toward human neuroblastoma SK-N-SH cells and leukemia K562 cells were respectively evaluated to explore the signaling pathway of PLA2-induced cell death. Upon exposure to PLA2, p38 mitogen-activated protein kinase (p38 MAPK) or c-Jun N-terminal kinase (JNK) activation, extracellularsignal-regulated protein kinase (ERK) inactivation, reactive oxygen species (ROS) generation, increase in intracellular Ca2+ concentration, the loss of mitochondrial membrane potential (ΔΨm), cytochrome c release and upregulation of Fas/FasL were found in SK-N-SH or K562 cells. N-Acetylcysteine (ROS scavenger), BAPTA-AM (Ca2+ chelator), SB202190 (p38 MAPK inhibitor) or SP600125 (JNK inhibitor) abrogated p38 MAPK or JNK activation and rescued cell viability, ΔΨm, cytochrome c release and suppressed Fas/FasL upregulation of PLA2-treated cells, but restored phosphorylation of ERK. Activated ERK was found to attenuate p38 MAPK-mediated upregulation of Fas/FasL. Besides, sustained JNK activation was also observed in SB202190/PLA2-treated K562 cells after exterminating p38 MAPK activation, but also retained the cytotoxicity of PLA2. Knockdown of p38 MAPK or JNK1 by siRNA proved that PLA2 induced Fas/FasL upregulation through p38 MAPK/ATF-2 or JNK1/c-Jun pathways in K562 cells. Furthermore, deprivation of catalytic activity could not diminish PLA2-induced cell death and Fas/FasL upregulation.
The cytotoxicity of arachidonic acid (AA) and lysophosphatidylcholine (LPC) was not related to the expression of Fas/FasL. The results showed that the cytotoxicity of AA is mediated through mitochondria-dependent death pathway, eliciting by AA-induced ROS generation and Ca2+-evoked activation of p38 MAPK and JNK. Besides, ERK activation abrogated by U0126 improved the ability of AA-mediated Fas/FasL upregulation in K562 cells. Taken together, our results indicate that PLA2-induced cell death is through Ca2+- and ROS evoked p38 MAPK or JNK activation. Upregulation of Fas/FasL partially involves in cytotoxicity of PLA2.
中文摘要 …………………………………………………… 5
英文摘要 …………………………………………………… 7
緒論 …………………………………………………… 9
圖1~圖4 …………………………………………………… 19
縮寫表 …………………………………………………… 23
實驗材料 …………………………………………………… 24
實驗方法 …………………………………………………… 26
I. PLA2 對 SK-N-SH 細胞的毒殺機制 …………………… 35
實驗目的 …………………………………………………… 36
結果 …………………………………………………… 38
圖5~圖19 …………………………………………………… 44
II. AA 對 SK-N-SH 細胞的毒殺機制 ……………………… 59
實驗目的 …………………………………………………… 60
結果 …………………………………………………… 62
圖20~圖33 …………………………………………………… 68
III. PLA2 對 K562 細胞的毒殺機制 ……………………… 82
實驗目的 …………………………………………………… 83
結果 …………………………………………………… 85
圖34~圖52 …………………………………………………… 94
IV. AA 對 K562 細胞的毒殺機制 ………………………… 113
實驗目的 …………………………………………………… 114
結果 …………………………………………………… 116
圖53~圖68 ………………………………………………… 121
討論 …………………………………………………… 137
參考文獻 …………………………………………………… 143
歷年發表作品 ……………………………………………… 172
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