MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
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DOI：
10.1371/journal.pone.0139254
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Andreeff M
中科院分区：
文献类型：
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作者：
Borthakur G;Duvvuri S;Ruvolo V;Tripathi DN;Piya S;Burks J;Jacamo R;Kojima K;Ruvolo P;Fueyo-Margareto J;Konopleva M;Andreeff M
MDM2(小鼠双分钟2)抑制剂可以激活p53并以非遗传毒性的方式诱导细胞凋亡，目前正在开发用于治疗白血病的临床药物。P53可以调节其他程序性细胞死亡途径，包括转录和非转录的自噬。我们研究了一类MDM2抑制剂Nutlin 3a在急性白血病中诱导自噬的作用。Nutlin 3a以P53依赖的方式诱导自噬，AMPK的转录激活是关键，因为这一作用在AMPK/-小鼠胚胎成纤维细胞中被取消。Nutlin 3a诱导的自噬似乎是促凋亡的，因为药物(巴菲霉素)或基因抑制(BECLIN1基因敲除)的自噬损害了Nutlin 3a诱导的细胞凋亡。
MDM2 (mouse double minute 2) inhibitors that activate p53 and induce apoptosis in a non-genotoxic manner are in clinical development for treatment of leukemias. P53 can modulate other programmed cell death pathways including autophagy both transcriptionally and non-transcriptionally. We investigated autophagy induction in acute leukemia by Nutlin 3a, a first-in-class MDM2 inhibitor. Nutlin 3a induced autophagy in a p53 dependent manner and transcriptional activation of AMP kinase (AMPK) is critical, as this effect is abrogated in AMPK -/- mouse embryonic fibroblasts. Nutlin 3a induced autophagy appears to be pro-apoptotic as pharmacological (bafilomycin) or genetic inhibition (BECLIN1 knockdown) of autophagy impairs apoptosis induced by Nutlin 3a.