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.
Highlights
A change in energy metabolism is listed as one of the ten hallmarks of cancer.[1]
Consistent with a role for Pyruvate kinase isoenzyme type M2 (PKM2) in extracellular acidification, si-PKM2 transfected cells exhibited lower levels of the extracellular acidification rate (ECAR) after treatment with glucose or oligomycin compared with the negative control: measurements of glycolysis under basal conditions and the maximum glycolytic capacity were both inhibited when PKM2 was decreased (Fig.1F)
Recent studies have shown that pyruvate kinase, the enzyme that catalyzes the last step of glycolysis,[7] functions as a regulator of cancer cell metabolism, which is exemplified high glucose consumption and lactate production.[15]
Summary
A change in energy metabolism is listed as one of the ten hallmarks of cancer.[1] Under aerobic conditions, normal differentiated cells extract energy from glucose through oxidative phosphorylation, but tumor cells metabolize more glucose to lactate. This phenomenon, termed the Warburg effect (aerobic glycolysis), is important for tumor cell proliferation.[2, 3] Glioma, the most common primary brain tumor, exhibits the Warburg effect.[4,5,6] few studies on glioma cell metabolism have been reported. The PKM1 promotes oxidative phosphorylation, whereas PKM2 primarily contributes to aerobic glycolysis
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