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GCN5-ERK lactylation-phosphorylation loop amplifies lactate-driven cancer progression.

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Lactate accelerates cancer by activating the MAPK pathway via ERK lactylation. This study identifies GCN5 as the enzyme responsible and a peptide inhibitor that reduces tumor growth in KRAS-mutant cancers.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The Warburg effect increases lactate production, promoting cancer progression through unclear mechanisms.
  • Lactate's role in cancer progression necessitates understanding its molecular drivers.

Purpose of the Study:

  • To elucidate the molecular mechanism linking lactate to cancer progression.
  • To identify key enzymes and pathways involved in lactate-mediated cancer growth.
  • To develop and test a therapeutic strategy targeting this pathway.

Main Methods:

  • Investigated the role of lactate in activating the MAPK pathway.
  • Identified GCN5 as the lactyltransferase for ERK (Extracellular signal-regulated kinases).
  • Assessed the impact of ERK lactylation on ERK-MEK interactions and activation.
  • Developed and tested a cell-penetrating peptide inhibitor of ERK lactylation in cancer models.

Main Results:

  • Lactate activates the MAPK pathway via ERK lactylation, promoting cancer progression.
  • GCN5 was identified as the lactyltransferase responsible for ERK lactylation.
  • Activated ERK phosphorylates GCN5, creating a positive feedback loop.
  • ERK lactylation at K231 weakens ERK-MEK interaction, enhancing ERK dimerization and activation.
  • The developed peptide inhibitor impaired tumor growth in KRAS-mutant cancer models.

Conclusions:

  • Lactate accelerates cancer progression via an ERK-GCN5 lactylation-phosphorylation cascade.
  • Targeting ERK lactylation presents a potential therapeutic strategy for RAS-ERK-driven cancers.