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Glutamine potentiates TNF-alpha-induced tumor cytotoxicity

E Obrador1, J Carretero, J M Esteve

  • 1Departamento de Fisiología, Universidad de Valencia, Valencia, Spain

Free Radical Biology & Medicine
|August 28, 2001
PubMed

Insights

L-glutamine sensitizes tumor cells to TNF-alpha. Glutamine oxidation depletes mitochondrial glutathione, triggering apoptosis. Restoring glutathione levels prevents this TNF-alpha-induced cell death.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • L-glutamine (Gln) enhances tumor necrosis factor (TNF)-alpha-induced cancer cell death.
  • Understanding the precise mechanism of this sensitization is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the cell death mechanisms induced by TNF-alpha in Gln-sensitized tumor cells.
  • To elucidate the role of mitochondrial glutathione (mtGSH) and reactive oxygen intermediates (ROIs) in this process.

Main Methods:

  • Ehrlich ascites tumor (EAT)-bearing mice were fed a Gln-enriched diet (GED).
  • Mitochondrial glutathione levels, transmembrane potential (MMP), and cytochrome c release were measured.
  • Tumor cells were cultured with Gln-enriched medium and buthionine sulfoximine (BSO) or treated with GSH ester.
  • Bcl-2 gene expression was manipulated in tumor cells.

Main Results:

  • High Gln oxidation in GED mice selectively depleted mtGSH by ~42% via glutamate-induced inhibition of GSH transport.
  • TNF-alpha further reduced mtGSH (~65% depletion), decreased MMP, and induced mitochondrial membrane permeabilization and cytochrome c release.
  • Similar mitochondrial events occurred in Gln-enriched medium with BSO-induced GSH inhibition.
  • Enforced bcl-2 expression did not prevent Gln- and TNF-alpha-induced death under mtGSH depletion.
  • GSH ester addition restored mtGSH levels and preserved cell viability.

Conclusions:

  • Glutamine oxidation and TNF-alpha synergistically deplete mtGSH, initiating apoptotic cell death.
  • Mitochondrial glutathione status is a critical determinant of TNF-alpha-induced apoptosis in tumor cells.
  • Targeting mitochondrial glutathione represents a potential therapeutic strategy for enhancing cancer treatment efficacy.

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