PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop.
PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop.
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PKM2 通过涉及 let-7a/c-Myc/hnRNPA1 反馈回路的机制促进神经胶质瘤中的葡萄糖代谢和细胞生长
DOI：
10.18632/oncotarget.3514
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发表时间：
2015-05-30
期刊：
影响因子：
--
通讯作者：
You Y
中科院分区：
文献类型：
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作者：
Luan W;Wang Y;Chen X;Shi Y;Wang J;Zhang J;Qian J;Li R;Tao T;Wei W;Hu Q;Liu N;You Y
在有氧或缺氧条件下，肿瘤细胞比非肿瘤细胞代谢更多的葡萄糖为乳酸。丙酮酸激酶同工酶M2（PKM 2）是肿瘤细胞有氧糖酵解的关键。我们建立了let-7a/c-Myc/hnRNPA 1/PKM 2信号在胶质瘤细胞葡萄糖代谢中的作用。通过siRNA去除PKM 2抑制胶质瘤细胞中的细胞增殖和有氧糖酵解。C-Myc促进hnRNPA 1表达的上调、hnRNPA 1与PKM前体mRNA的结合以及随后PKM 2的形成。该途径被功能性靶向c-Myc的microRNA let-7a下调，而hnRNPA 1阻断let-7a的生物合成以抵消其下调c-Myc/hnRNPA 1/PKM 2信号通路的能力。使用神经胶质瘤异种移植模型验证let-7a对c-Myc/hnRNPA 1/PKM 2的下调。这些结果提示let-7a、c-Myc和hnRNPA 1形成反馈环，从而调控PKM 2的表达来调节胶质瘤细胞的糖代谢。这些发现阐明了一个新的途径介导的有氧糖酵解在胶质瘤和治疗干预提供了一个有吸引力的潜在目标。
Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than non-tumor cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a/c-Myc/hnRNPA1/PKM2 signaling in glioma cell glucose metabolism. PKM2 depletion via siRNA inhibits cell proliferation and aerobic glycolysis in glioma cells. C-Myc promotes up-regulation of hnRNPA1 expression, hnRNPA1 binding to PKM pre-mRNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a, which functionally targets c-Myc, whereas hnRNPA1 blocks the biogenesis of let-7a to counteract its ability to downregulate the c-Myc/hnRNPA1/PKM2 signaling pathway. The down-regulation of c-Myc/hnRNPA1/PKM2 by let-7a is verified using a glioma xenograft model. These results suggest that let-7a, c-Myc and hnRNPA1 from a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of glioma cells. These findings elucidate a new pathway mediating aerobic glycolysis in gliomas and provide an attractive potential target for therapeutic intervention.