Pyruvate Kinase M2 and Cancer Metabolism

Pyruvate kinase M2 (PKM2) occupies a central role in cancer metabolism, catalysing the final and rate-limiting step of glycolysis by converting phosphoenolpyruvate to pyruvate. It exists in high-activity tetrameric and low-activity dimeric forms, and the balance between these oligomeric states dictates whether glucose carbons are directed towards ATP production or diverted into biosynthetic pathways. In many tumours, PKM2 preferentially adopts the dimeric configuration, facilitating accumulation of glycolytic intermediates that support nucleotide, amino acid and lipid synthesis and underpin the Warburg effect, whereby cells rely on aerobic glycolysis despite sufficient oxygen. Beyond its metabolic function, dimeric PKM2 translocates to the nucleus to act as a protein kinase or co-activator of transcription factors, thereby influencing gene programmes that drive proliferation, angiogenesis and survival. Post-translational modifications such as phosphorylation, acetylation and SUMOylation further regulate PKM2’s oligomerisation, subcellular localisation and stability. Through these multifaceted roles, PKM2 integrates signalling from hypoxia, growth factors and oncogenes to reprogram cellular metabolism, making it both a biomarker of tumour progression and a promising target for therapeutic intervention.

Research from Nature Portfolio

Recent studies have uncovered new regulatory axes modulating PKM2 in cancer. In colorectal carcinoma models, the RNA exonuclease MYG1 enhances PKM2 phosphorylation by recruiting a chaperone-kinase complex, stabilising the enzyme and establishing a feed-forward loop with MYC that drives glycolysis, suppresses oxidative phosphorylation and inhibits mitochondrial apoptosis. In hepatocellular carcinoma, the anti-apoptotic factor PARP14 was shown to inhibit JNK1-dependent activation of PKM2, maintaining its low-activity state and thus sustaining aerobic glycolysis and resistance to cell death. Investigations in brain tumours have revealed that the phosphatase Cdc25A dephosphorylates PKM2 at a critical serine residue, enabling nuclear β-catenin transactivation and c-Myc–mediated upregulation of glycolytic genes, forming a positive feedback loop that promotes tumour growth and malignancy.

Pyruvate Kinase M2 and Cancer Metabolism publication trend

The graph below shows the total number of articles in pyruvate kinase m2 and cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Warburg effect: Preference of cancer cells for aerobic glycolysis over oxidative phosphorylation even under normoxic conditions.

Oligomerisation: Assembly of protein subunits into functional multi-unit complexes, for example PKM2 dimers and tetramers.

SUMOylation: Covalent attachment of small ubiquitin-like modifier proteins to lysine residues, altering target protein function, localisation or stability.

Vasculogenic mimicry: Formation of vessel-like networks by aggressive tumour cells independent of endothelial cell angiogenesis.

Oxidative phosphorylation (OXPHOS): Mitochondrial process of ATP synthesis through electron transport and reduction of oxygen to water.

References

1. ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment. Molecular Cancer (2024).
2. MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration. Nature Communications (2024).
3. PKM2 allosteric converter: A self-assembly peptide for suppressing renal cell carcinoma and sensitizing chemotherapy. Biomaterials (2023).
4. PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. Nature Communications (2015).
5. PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nature Communications (2016).
6. PKM2, function and expression and regulation. Cell & Bioscience (2019).