AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia.
AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia.
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DOI：
10.1158/1535-7163.mct-10-0777
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发表时间：
2011-03
影响因子：
5.7
通讯作者：
Barredo JC
中科院分区：
文献类型：
--
作者：
Kuznetsov JN;Leclerc GJ;Leclerc GM;Barredo JC
AICAr 是一种细胞渗透性核苷酸，已在体内和体外用于激活 AMPK。我们之前的研究结果表明，AICAr 作为单一药物可在急性淋巴细胞白血病 (ALL) 细胞系中诱导剂量和时间依赖性生长抑制。此外，AICAr 与抗叶酸剂（甲氨蝶呤 (MTX) 或培美曲塞）的组合已被证明可进一步增强 AMPK 激活，并导致对白血病和其他恶性细胞类型产生更大的细胞毒性和生长抑制。我们在此提供的数据表明，在 Bp-和 T-ALL 中，持续的 ER 应激是 AICAr 与一碳代谢抑制剂 MTX 组合协同诱导细胞死亡的主要机制，诱导几种导致细胞凋亡的未折叠蛋白反应标记物就证明了这一点。我们还首次证明 AIAr 与 MTX 联合显着诱导 ALL 中的 Akt 磷酸化。在这些条件下，同时抑制 AMPK 的细胞拮抗剂 Akt，导致 AMPK 活性进一步上调，并减轻 AICAr 加 MTX 诱导的 ER 应激和细胞凋亡。因此，我们还证明 AMPK 的同时激活实际上可以将细胞从 AICAr 加 MTX 诱导的 ER 应激和细胞凋亡中拯救出来。我们的数据表明，AMPK 激活对细胞死亡或存活的影响根据其与相关致癌途径的信号传导改变而有所不同，并提供了对 AMPK 激活所报道的矛盾的促凋亡与促生存效应的深入了解。
AICAr is a cell-permeable nucleotide that has been used in vivo and in vitro to activate AMPK. Our previous findings have shown that AICAr as a single agent induces dose- and time-dependent growth inhibition in acute lymphoblastic leukemia (ALL) cell lines. In addition, the combination of AICAr with antifolates (methotrexate (MTX) or pemetrexed) has been shown to further potentiate AMPK activation and to lead to greater cytotoxicity and growth inhibition in leukemia and other malignant cell types. Our data presented herein demonstrate that sustained ER stress is the predominant mechanism behind the synergistic induction of cell death by the combination of AICAr plus the inhibitor of one-carbon metabolism, MTX, in Bp- and T-ALL, as evidenced by induction of several unfolded protein response markers leading to apoptosis. We also show for the first time that AICAr in combination with MTX significantly induces Akt phosphorylation in ALL. Under these conditions, the concomitant inhibition of Akt, a cellular antagonist of AMPK, leads to further up-regulation of AMPK activity and alleviates AICAr plus MTX-induced ER stress and apoptosis. Therefore, we also demonstrate that the concomitant activation of AMPK actually rescues the cells from AICAr plus MTX-induced ER stress and apoptosis. Our data suggest that the effects of AMPK activation on cell death or survival differ contextually depending on its signaling alterations with related oncogenic pathways and provide insight into the reported paradoxical pro-apoptotic vs. pro-survival effects of AMPK activation.