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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Wenkang Luan1,*, Yingyi Wang1,*, Xincheng Chen1,*, Yan Shi1,*, Jiajia Wang1, Junxia Zhang1, Jin Qian2, Ri Li1, Tao Tao1, Wenjin Wei1, Qi Hu1, Ning Liu1 and Yongping You1
1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2 Department of Neurosurgery, People’s Hospital of Xuancheng City, Anhui, China
* These authors contributed equally to this work
Yongping You, email:
Keywords: let-7a microRNA, c-Myc, hnRNPA1, PKM2, glucose metabolism, aerobic glycolysis, glioma
Received: October 08, 2014 Accepted: February 04, 2015 Published: February 10, 2015
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.
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