p53-regulated autophagy is controlled by glycolysis and determines cell fate.
p53-regulated autophagy is controlled by glycolysis and determines cell fate.
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DOI：
10.18632/oncotarget.5218
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Maki CG
中科院分区：
文献类型：
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作者：
Duan L;Perez RE;Davaadelger B;Dedkova EN;Blatter LA;Maki CG
肿瘤抑制因子p53调节决定细胞命运的下游靶点。典型的p53功能包括诱导细胞凋亡、生长停滞和衰老。非典型的p53功能包括其促进或抑制自噬的能力以及其调节代谢的能力。自噬和/或代谢调节在多大程度上决定细胞命运的p53是不清楚的。为了解决这一问题，我们比较了对p53激活剂Nutlin-3a引起的细胞凋亡具有抗性或敏感性的细胞。在抗性细胞中，Nutlin-3a处理后糖酵解得以维持，并且活化的p53促进促生存自噬。相反，在凋亡敏感细胞中，激活的p53通过抑制糖酵解途径基因增加超氧化物水平并抑制糖酵解。糖酵解抑制和增加超氧化物抑制自噬囊泡成熟所必需的ATG基因。抑制糖酵解增加了超氧化物，并阻断了耐糖酵解细胞的自噬，导致p62依赖性caspase-8激活。最后，用2-DG或自噬抑制剂氯喹或巴弗洛霉素A1处理使耐药细胞对Nutlin-3a诱导的凋亡敏感。总之，这些发现揭示了糖酵解和自噬之间的新联系，这些联系决定了对p53的响应的凋亡敏感性。具体而言，这些发现表明：1）糖酵解通过限制超氧化物水平和维持自噬囊泡成熟所需的ATG基因的表达在自噬中起着至关重要的作用，2）p53可以根据糖酵解的状态促进或抑制自噬，以及3）抑制保护性自噬可以扩大对Nutlin-3a诱导的凋亡敏感的细胞的宽度。
The tumor suppressor p53 regulates downstream targets that determine cell fate. Canonical p53 functions include inducing apoptosis, growth arrest, and senescence. Non-canonical p53 functions include its ability to promote or inhibit autophagy and its ability to regulate metabolism. The extent to which autophagy and/or metabolic regulation determines cell fate by p53 is unclear. To address this, we compared cells resistant or sensitive to apoptosis by the p53 activator Nutlin-3a. In resistant cells, glycolysis was maintained upon Nutlin-3a treatment, and activated p53 promoted prosurvival autophagy. In contrast, in apoptosis sensitive cells activated p53 increased superoxide levels and inhibited glycolysis through repression of glycolytic pathway genes. Glycolysis inhibition and increased superoxide inhibited autophagy by repressing ATG genes essential for autophagic vesicle maturation. Inhibiting glycolysis increased superoxide and blocked autophagy in apoptosis-resistant cells, causing p62-dependent caspase-8 activation. Finally, treatment with 2-DG or the autophagy inhibitors chloroquine or bafilomycin A1 sensitized resistant cells to Nutlin-3a-induced apoptosis. Together, these findings reveal novel links between glycolysis and autophagy that determine apoptosis-sensitivity in response to p53. Specifically, the findings indicate 1) that glycolysis plays an essential role in autophagy by limiting superoxide levels and maintaining expression of ATG genes required for autophagic vesicle maturation, 2) that p53 can promote or inhibit autophagy depending on the status of glycolysis, and 3) that inhibiting protective autophagy can expand the breadth of cells susceptible to Nutlin-3a induced apoptosis.