ERK1/2 acts as a switch between necrotic and apoptotic cell death in ether phospholipid edelfosine-treated glioblastoma cells
ERK1/2 acts as a switch between necrotic and apoptotic cell death in ether phospholipid edelfosine-treated glioblastoma cells
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DOI：
10.1016/j.phrs.2015.02.007
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发表时间：
2015-05-01
影响因子：
9.3
通讯作者：
Mollinedo, Faustino
中科院分区：
文献类型：
--
作者：
Melo-Lima, Sara;Lopes, Maria C.;Mollinedo, Faustino
胶质母细胞瘤的特点是组成性细胞凋亡抵抗和生存信号表达，但矛盾的是，它是一种容易坏死的肿瘤。将人U118胶质母细胞瘤细胞与抗肿瘤烷基磷脂类似物edelfosine一起孵育，可诱导坏死细胞死亡，而凋亡很少。选择性MEK1/2抑制剂U0126（抑制MEK1/2介导的ERK1/2激活）对U118细胞进行预孵育，在edelfosine处理后，导致细胞从坏死转变为caspase依赖性凋亡。U0126和edelfosine联合处理完全抑制ERK1/2磷酸化，导致RIPK1和RelA/NF-kappa B降解，同时强烈激活caspase-3和-8。这种凋亡反应伴随着线粒体跨膜电位损失、Bcl-x(L)降解和caspase-9活化等固有凋亡途径的激活。当烷基磷脂类似物在低微摩尔范围内使用时，抑制ERK磷酸化也会导致雪绒花诱导的凋亡急剧增加，这表明ERK磷酸化在雪绒花处理的U118细胞中起着凋亡细胞死亡的有效调节作用。这些数据表明，抑制MEK1/2-ERK1/2信号通路可高度增强雪绒花诱导的胶质母细胞瘤U118细胞凋亡，并将雪绒花诱导的细胞死亡类型从坏死转变为凋亡。(C) 2015 Elsevier Ltd.版权所有。
Glioblastoma is characterized by constitutive apoptosis resistance and survival signaling expression, but paradoxically is a necrosis-prone neoplasm. Incubation of human U118 glioblastoma cells with the antitumor alkylphospholipid analog edelfosine induced a potent necrotic cell death, whereas apoptosis was scarce. Preincubation of U118 cells with the selective MEK1/2 inhibitor U0126, which inhibits MEK1/2 mediated activation of ERK1/2, led to a switch from necrosis to caspase-dependent apoptosis following edelfosine treatment. Combined treatment of U0126 and edelfosine totally inhibited ERK1/2 phosphorylation, and led to RIPK1 and RelA/NF-kappa B degradation, together with a strong activation of caspase-3 and -8. This apoptotic response was accompanied by the activation of the intrinsic apoptotic pathway with mitochondrial transmembrane potential loss, Bcl-x(L) degradation and caspase-9 activation. Inhibition of ERK phosphorylation also led to a dramatic increase in edelfosine-induced apoptosis when the alkylphospholipid analog was used at a low micromolar range, suggesting that ERK phosphorylation acts as a potent regulator of apoptotic cell death in edelfosine-treated U118 cells. These data show that inhibition of MEK1/2-ERK1/2 signaling pathway highly potentiates edelfosine-induced apoptosis in glioblastoma U118 cells and switches the type of edelfosine-induced cell death from necrosis to apoptosis. (C) 2015 Elsevier Ltd. All rights reserved.