Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway
Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway
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DOI：
10.1016/j.leukres.2014.11.006
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发表时间：
2015-02-01
影响因子：
2.7
通讯作者：
Pardee, Timothy S.
中科院分区：
文献类型：
--
作者：
Gmeiner, William H.;Jennings-Gee, Jamie;Pardee, Timothy S.
聚合氟嘧啶 F10 通过胸苷酸合酶和 DNA 拓扑异构酶 1 的双重靶向，在急性髓性白血病 (AML) 的临床前模型中表现出优异的抗白血病活性。在此，我们报道 F10 通过增强 Fas 和 Fas 配体 (FasL) 在质膜上的定位来激活 AML 细胞中的外在凋亡途径，同时降低总体脂筏水平，从而促进 Fas/FasL剩余脂筏中的共定位。 HMG-CoA 合酶抑制剂辛伐他汀与 F10 具有协同作用，并通过类似的细胞凋亡过程诱导细胞死亡。我们的结果与激活共同凋亡途径的多种过程一致，其特征是质膜中脂筏和 Fas/FasL 共定位的总体水平降低，包括可能在细胞生存和细胞死亡信号传导中发挥作用的剩余脂筏。 (C) 2014 Elsevier Ltd. 保留所有权利。
The polymeric fluoropyrimidine F10 displays excellent anti-leukemia activity in pre-clinical models of acute myelogenous leukemia (AML) through dual targeting of thymidylate synthase and DNA topoisomerase 1. Here we report that F10 activates the extrinsic apoptotic pathway in AML cells by enhancing localization of Fas and Fas ligand (FasL) at the plasma membrane and while reducing overall lipid raft levels promotes Fas/FasL co-localization in remaining lipid rafts. The HMG-CoA synthase inhibitor simvastatin was synergistic with F10 and induced cell death via similar apoptotic processes. Our results are consistent with diverse processes activating a common apoptotic pathway characterized by reduced overall levels of lipid rafts and Fas/FasL co-localization in the plasma membrane, including in remaining lipid rafts which may play a role in both cell-survival and cell death signaling. (C) 2014 Elsevier Ltd. All rights reserved.