鳥胺酸去羧化酶降低二甲亞碸所誘導類嗜中性白血球分化、活化以及細胞凋亡

鳥胺酸去羧化酶（ornithine decarboxylase; ODC）為多胺酸（polyamine）合成路徑的反應速率決定步驟，將鳥胺酸（L-ornithine）去羧化成腐胺（putrescine）以及二氧化碳進而生成亞精胺（spermidine）以及精胺（spermine），鳥胺酸去羧化酶在生物功能上也扮演著重要的角色，對於細胞的生長、發育、細胞凋亡以及細胞的分化等等生物功能，先前的研究都指出鳥胺酸去羧化酶會參與其中，過量的鳥胺酸去羧化酶與多胺類會抑制巨噬細胞的免疫反應，以及影響骨髓性白血球細胞的分化。本篇探討骨髓性白血球細胞的分化成嗜中性白血球時是否因為鳥胺酸去羧化酶的過量表現而影響了類嗜中性白血球的分化、活化以及死亡。首先我們使用dimethyl sulfoxide（DMSO）促進細胞分化，觀察到HL-60細胞存活率沒有因為加入DMSO而下降，接著利用劉氏染色、吞噬作用以及nitroblue tetrazolium（NBT）觀察到分化成類嗜中性白血球後細胞的形態和功能受到鳥胺酸去羧化酶的過度表現而受到了抑制。死亡方面，細胞凋亡的特徵像是凋亡小體的形成、染色質的片斷化以及細胞周期中SubG1 peak的形成都因為鳥胺酸去羧化酶得過量而延緩細胞的死亡。人類嗜中性白血球經由Fas訊息傳導路徑而走向死亡，在這裡我們也發現是鳥胺酸去羧化酶干擾Fas的表現而影響細胞的死亡，而Fas的下游蛋白caspase 8, t-bid, Bax, caspase 9, caspase 3的表現也因為鳥胺酸去羧化酶的表現增加有被抑制的現象，在這裡我們發現因為轉錄因子CCAAT/enhancer binding protein（C/EBP family protein）以及PU.1表現量下降而降低了細胞的分化和死亡。本篇探討鳥胺酸去羧化酶的過量表現影響了細胞的分化以及死亡而鳥胺酸去羧化酶可能是為其中一種干擾骨髓細胞分化而形成血癌的因子。

Ornithine decarboxylase (ODC), a tumor promoter, provokes cell proliferation, and inhibits cell death. A human leukemic cell line (designated HL-60) has been established from the peripheral blood leukocytes of a patient with acute promyelocytic leukemia. In past research we study ODC interferes with macrophage-like differentiation. Herein, we examine whether it functions during neutrophil-like differentiation. By using dimethyl-sulfoxide (DMSO) differentiated human promyelocytic HL-60, we discover cluster of differentiation molecule 11B (CD11B) is a granulocyte integrin as neutrophil differentiation marker and observe its nuclear morphology. Temporarily conventional expression of ODC represses polar compound-induced terminal myeloid differentiation and activation by Liu’s stain, phagocytosis and NBT assays. Furthermore, ODC overexpression reduced CD95/Fas and its transcription factor mRNA expression. Fas has known to induce neutrophil apoptosis. ODC-attenuated DMSO-induced cell death is through an extrinsic apoptosis pathway, includes Fas, caspase 8, t-Bid, Bax, caspase 9 and caspase 3 protein expression. Consequently we suggest that ODC inhibits DMSO-induced human neutrophil-like differentiation, activation and apoptotic cell death. These interrupting mechanisms may provide the possible reason of neutrophil immaturation and why leukemia is poor differentiation under abnormally not death.