PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop

Oncotarget. 2015 May 30;6(15):13006-18. doi: 10.18632/oncotarget.3514.

Abstract

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.

Keywords: PKM2; aerobic glycolysis; c-Myc; glioma; glucose metabolism; hnRNPA1; let-7a microRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Feedback, Physiological
  • Female
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology
  • Glucose / metabolism*
  • Glycolysis
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
  • Heterografts
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Pyruvate Kinase / genetics
  • Pyruvate Kinase / metabolism*
  • Signal Transduction
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • Transfection

Substances

  • Carrier Proteins
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Hnrnpa1 protein, mouse
  • MYC protein, human
  • Membrane Proteins
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Thyroid Hormones
  • hnRNPA1 protein, human
  • mirnlet7 microRNA, human
  • thyroid hormone-binding proteins
  • Pyruvate Kinase
  • Glucose