Positive feedback loop via HIF-1α lactylation driven by kynurenine promotes glycolysis

Area of Science:

• Biochemistry
• Cancer Metabolism
• Molecular Oncology

Background:

• Tryptophan metabolism is altered in oral squamous cell carcinoma (OSCC).
• Kynurenine (Kyn), a key tryptophan metabolite, accumulates in OSCC.
• The role of Kyn in tumor metabolic reprogramming is not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which Kyn drives metabolic reprogramming in OSCC.
• To identify Kyn as a metabolic signal promoting tumor progression.

Main Methods:

• Investigated the association between Kyn, AKT, mTOR, and HIF-1α.
• Analyzed the impact of Kyn on glycolytic enzyme expression and lactate production.
• Examined the role of lysine lactylation in stabilizing HIF-1α.

Main Results:

• Kyn functionally associates with AKT, enhancing mTOR phosphorylation and cap-dependent translation of HIF-1α.
• Elevated HIF-1α upregulates glycolytic enzymes, increasing glycolytic flux and lactate production.
• Lactate stabilizes HIF-1α via lysine lactylation, forming a feedback loop that enhances glycolysis and tumor expansion.

Conclusions:

• Kynurenine promotes glycolysis in OSCC through AKT/mTOR-mediated translational activation of HIF-1α.
• A reinforcing feedback loop involving Kyn, HIF-1α, and lactate enhances glycolytic activity.
• These findings reveal a link between tryptophan and glucose metabolism, suggesting therapeutic targets in OSCC.