Pyruvate kinase M2 (PKM2) is a central metabolic enzyme driving the Warburg effect in tumor growth. Previous investigations have demonstrated that PKM2 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification, which is a nutrient-sensitive post-translational modification. Here we found that unc-51 like autophagy activating kinase 1 (ULK1), a glucose-sensitive kinase, interacts with PKM2 and phosphorylates PKM2 at Ser333. Ser333 phosphorylation antagonizes PKM2 O-GlcNAcylation, promotes its tetramer formation and enzymatic activity, and decreases its nuclear localization. As PKM2 is known to have a nuclear role in regulating c-Myc, we also show that PKM2-S333 phosphorylation inhibits c-Myc expression. By downregulating glucose consumption and lactate production, PKM2 pS333 attenuates the Warburg effect. Through mouse xenograft assays, we demonstrate that the phospho-deficient PKM2-S333A mutant promotes tumor growth in vivo. In conclusion, we identified a ULK1-PKM2-c-Myc axis in inhibiting breast cancer, and a glucose-sensitive phosphorylation of PKM2 in modulating the Warburg effect.
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http://dx.doi.org/10.1038/s41388-024-03035-y | DOI Listing |
Proc Natl Acad Sci U S A
January 2025
ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
Understanding the role of metabolic processes during inner ear development is essential for identifying targets for hair cell (HC) regeneration, as metabolic choices play a crucial role in cell proliferation and differentiation. Among the metabolic processes, growing evidence shows that glucose metabolism is closely related to organ development. However, the role of glucose metabolism in mammalian inner ear development and HC regeneration remains unclear.
View Article and Find Full Text PDFCell Rep
January 2025
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; Center for Research in Inflammatory Diseases, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil. Electronic address:
Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Department of Pharmacy-(DIFAR), University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy.
The retinal pigment epithelium (RPE) contributes to retinal homeostasis, and its metabolic dysfunction is implied in the development of retinal degenerative disease. The isoform M2 of pyruvate kinase (PKM2) is a key factor in cell metabolism, and its function may be affected by insulin-like growth factor 1 (IGF-1). This study aims to investigate the effect of IGF-1 on PKM2 modulation of RPE cells and whether co-treatment with klotho may preserve it.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Substantial loss of cardiomyocytes during heart attacks and onset of other cardiovascular diseases is a major cause of mortality. Preservation of cardiomyocytes during cardiac injury would be the most effective strategy to manage these diseases in clinic. However, there is no effective treatment strategy that is able to prevent cardiomyocyte loss.
View Article and Find Full Text PDFBiomedicines
December 2024
Departamento de Ciência Básica, Instituto de Saúde de Nova Fribrugo, Universidade Federal Fluminense, Nova Friburgo 28625-650, RJ, Brazil.
Pyruvate kinase M2, a central regulator of cancer cell metabolism, has garnered significant attention as a promising target for disrupting the metabolic adaptability of tumor cells. This study explores the potential of the Mannich base derived from lawsone () to interfere with PKM2 enzymatic activity both in vitro and in silico. The antiproliferative potential of was tested using MTT assay in various cell lines, including SCC-9, Hep-G2, HT-29, B16-F10, and normal human gingival fibroblast (HGF).
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