Involvement of c-Jun NH2-terminal kinase activation and c-Jun in the induction of apoptosis by the ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine
Involvement of c-Jun NH2-terminal kinase activation and c-Jun in the induction of apoptosis by the ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine
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DOI：
10.1124/mol.53.4.602
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发表时间：
1998-04-01
影响因子：
3.6
通讯作者：
Mollinedo, F
中科院分区：
文献类型：
--
作者：
Gajate, C;Santos-Beneit, A;Mollinedo, F
醚磷脂 1-O-十八烷基-2-O-甲基-rac-甘油-3-磷酸胆碱 (ET-18-OCH3；edelfosine) 是人类肿瘤细胞凋亡的有效诱导剂。我们发现 ET-18-OCH3 诱导的细胞凋亡与 c-Jun NH2 末端激酶 (JNK) 信号传导的激活有关。将 ET-18-OCH3 添加到不同的人类白血病细胞（HL-60、U937 和 Jurkat）中，这些细胞在 ET-18-OCH3 处理后经历快速凋亡，诱导 c-jun mRNA 水平显着且持续的增加，这与激活蛋白 1 转录因子的激活相关。我们发现 ET-18-OCH3 诱导 HL-60 细胞中 JNK 的持续激活，这种激活在细胞凋亡开始之前就被检测到，后者通过 DNA 碎片和质膜外叶上磷脂酰丝氨酸的出现来评估。 HL-60 单核细胞/巨噬细胞分化和 ET-18-OCH3 介导的细胞凋亡后 JNK 的诱导通过不同的激活模式（瞬时激活模式和持续激活模式）来区分。不能诱导细胞凋亡的ET-18-OCH3类似物未能激活JNK。在 K562 细胞中未检测到 ET-18-OCH3 依赖性 JNK 激活，该细胞在用 ET-18-OCH3 处理后未发生凋亡。佛波醇肉豆蔻酸酯乙酸酯抑制 ET-18-OCH3 诱导的细胞凋亡并持续 JNK 激活；因此，ET-18-OCH3 持续激活 JNK 与这种醚磷脂诱导细胞凋亡的能力有关。此外，针对 c-jun 的反义寡核苷酸可阻断 ET-18-OCH3 诱导的细胞凋亡，表明 c-Jun 在这种细胞凋亡反应中发挥作用。这些数据表明 JNK 激活和 c-Jun 参与 ET-18-OCH3 诱导的细胞凋亡。
The ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3; edelfosine) is a potent inducer of apoptosis in human tumor cells. We show that ET-18-OCH3-induced apoptosis is associated with activation of the c-Jun NH2-terminal kinase (JNK) signaling. The addition of ET-18-OCH3 to distinct human leukemic cells (HL-60, U937, and Jurkat), which undergo rapid apoptosis on treatment with ET-18-OCH3, induced a dramatic and sustained increase in the of c-jun mRNA level that was associated with activation of activator protein-1 transcription factor. We found that ET-18-OCH3 induced a persistent activation of JNK in HL-60 cells that was detected before the onset of apoptosis, the latter being assessed by DNA fragmentation and by the appearance of phosphatidylserine on the external leaflet of the plasma membrane. The inductions of JNK after HL-60 monocyte/macrophage differentiation and ET-18-OCH3-mediated apoptosis were distinguished by the different activation patterns, transient versus persistent, respectively. ET-18-OCH3 analogues unable to induce apoptosis failed to activate JNK. ET-18-OCH3-dependent JNK activation was not detected in K562 cells, which did not undergo apoptosis on treatment with ET-18-OCH3. Phorbol myristate acetate inhibited both ET-18-OCH3-induced apoptosis and sustained JNK activation; thus, persistent JNK activation by ET-18-OCH3 is associated with the capacity of this ether phospholipid to induce apoptosis. Furthermore, antisense oligonucleotides directed against c-jun blocked ET-18-OCH3-induced apoptosis, indicating a role for c-Jun in this apoptotic response. These data indicate that JNK activation and c-Jun are involved in the induction of apoptosis by ET-18-OCH3.