MDM2抑制剂Nutlin 3a通过激活AMP激酶在急性白血病中诱导p53依赖性自噬。
MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation.
作者信息
Borthakur Gautam, Duvvuri Seshagiri, Ruvolo Vivian, Tripathi Durga Nand, Piya Sujan, Burks Jared, Jacamo Rodrigo, Kojima Kensuke, Ruvolo Peter, Fueyo-Margareto Juan, Konopleva Marina, Andreeff Michael
机构信息
Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
Centre for Translational Cancer Research, Institute for Biosciences & Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.
出版信息
PLoS One. 2015 Oct 6;10(10):e0139254. doi: 10.1371/journal.pone.0139254. eCollection 2015.
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.
能以非基因毒性方式激活p53并诱导凋亡的MDM2（小鼠双微体2）抑制剂正处于治疗白血病的临床开发阶段。p53可通过转录和非转录方式调节包括自噬在内的其他程序性细胞死亡途径。我们研究了首个MDM2抑制剂Nutlin 3a对急性白血病自噬的诱导作用。Nutlin 3a以p53依赖的方式诱导自噬，且AMP激酶（AMPK）的转录激活至关重要，因为在AMPK基因敲除的小鼠胚胎成纤维细胞中这种效应会消失。Nutlin 3a诱导的自噬似乎具有促凋亡作用，因为自噬的药理学抑制（巴弗洛霉素）或基因抑制（BECLIN1基因敲低）会损害Nutlin 3a诱导的凋亡。
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