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TRAP1 Inhibition Increases Glutamine Synthetase Activity in Glutamine Auxotrophic Non-small Cell Lung Cancer Cells

Vu T A Vo1,2, Jong-Whan Choi1, Ai N H Phan1,2

  • 1Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.

Anticancer Research
|March 31, 2018
PubMed
Abstract

Insights

Tumor necrosis factor receptor-associated protein 1 (TRAP1) inhibitor gamitrinib-triphenylphosphonium (G-TPP) effectively targets glutamine-dependent non-small cell lung cancer (NSCLC) cells. This G-TPP treatment induces cell death by increasing glutamine synthetase activity and causing energy depletion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Cancer cells exhibit varying dependencies on glutamine.
  • Non-small cell lung cancer (NSCLC) presents diverse metabolic adaptations.
  • Glutamine metabolism is a critical factor in cancer cell survival.

Purpose of the Study:

  • To investigate the differential susceptibility of glutamine-independent and glutamine-dependent NSCLC cells to TRAP1 inhibitor G-TPP.
  • To elucidate the role of TRAP1 in regulating glutamine metabolism in NSCLC.
  • To assess the therapeutic potential of targeting TRAP1 in glutamine-addicted cancers.

Main Methods:

  • Cell viability and proliferation assays (MTT, colony formation) under glutamine deprivation and G-TPP treatment.
  • Western blot and quantitative PCR for protein and mRNA expression analysis.
  • Colorimetric assay to determine glutamine synthetase (GS) activity.

Main Results:

  • NSCLC cells were categorized into glutamine-independent and glutamine-dependent phenotypes under glutamine-depleted conditions.
  • G-TPP treatment significantly increased GS activity in glutamine-dependent cells.
  • G-TPP induced cell death in glutamine-dependent NSCLC cells, evidenced by energy depletion (phosphorylated AMPK).

Conclusions:

  • TRAP1 inhibition impacts glutamine metabolism via GS activity.
  • TRAP1 represents a promising therapeutic target for glutamine-dependent NSCLC.
  • Understanding cancer cell glutamine addiction is crucial for developing targeted therapies.
Keywords:
Glutamine metabolismTRAP1gamitrinib-triphenylphosphoniumglutamine synthetaselung cancer

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