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Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor

Rosario Yerbes1,2, Rocío Mora-Molina1, F Javier Fernández-Farrán1

  • 1Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Avda Américo Vespucio 24, 41092, Sevilla, Spain.

Cell Death & Disease
|October 27, 2022
PubMed

Insights

Glutamine-addicted tumor cells activate a novel cell death pathway when starved of glutamine. This GCN2-regulated mechanism involves TRAIL-R2 and caspase-8, leading to apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Metabolic Pathways

Background:

  • Cancer cells exhibit altered glutamine metabolism, creating dependence for growth and survival.
  • Understanding cell death mechanisms in these addicted cells is crucial for therapeutic strategies.

Purpose of the Study:

  • To elucidate the cell death mechanism in glutamine-addicted tumor cells upon glutamine metabolism limitation.
  • To identify key molecular players and signaling pathways involved in this process.

Main Methods:

  • Induction of glutamine starvation in tumor cells.
  • Analysis of apoptotic pathways, including FADD, caspase-8, and TRAIL-R2.
  • Investigation of the role of general control nonderepressible-2 kinase (GCN2) and its signaling.
  • Assessment of FLICE-inhibitory protein (FLIP) regulation.
  • Pharmacological inhibition of transaminases and supplementation with non-essential amino acids (NEAA) and α-ketoglutarate.

Main Results:

  • Glutamine starvation triggers FADD, caspase-8, and mitochondria-dependent apoptosis involving TRAIL-R2.
  • GCN2 activation in glutamine-depleted cells upregulates TRAIL-R2, activates caspase-8, and induces apoptosis.
  • Methionine starvation-induced GCN2 signaling also promotes TRAIL-R2 upregulation and apoptosis.
  • Pharmacological inhibition of transaminases activates a GCN2/TRAIL-R2-dependent apoptotic pathway, sensitive to NEAA.
  • Metabolic stress leads to GCN2-independent FLIP downregulation, facilitating caspase-8 activation.
  • Downregulation of FLIPL and apoptosis are inhibited by α-ketoglutarate.

Conclusions:

  • A novel GCN2-regulated cell death mechanism is activated in glutamine-depleted tumor cells.
  • This pathway involves the TRAIL-R2-mediated activation of the extrinsic apoptotic pathway.
  • Targeting glutamine metabolism can induce apoptosis through this newly identified mechanism.

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