Glutamine deprivation-mediated cell shrinkage induces ligand-independent CD95 receptor signaling and apoptosis

Cell Death Differ. 2001 Oct;8(10):1004-13. doi: 10.1038/sj.cdd.4400902.


Cell shrinkage and loss of cell viability by apoptosis have been examined in cultured CD95(Fas/Apo-1)-expressing leukemia-derived CEM and HL-60 cells subjected to acute deprivation of glutamine, a major compatible osmolyte engaged in cell volume control. Glutamine deprivation-mediated cell shrinkage promoted a ligand-independent activation of the CD95-mediated apoptotic pathway. Cell transfection with plasmids expressing FADD-DN or v-Flip viral proteins pointed to a functional clustering of CD95 receptors at the cell surface with activation of the 'extrinsic pathway' caspase cascade. Accordingly, cell shrinkage did not induce apoptosis in CD95 receptor-negative lymphoma L1210 cells. Replacement of glutamine with surrogate compatible osmolytes counteracted cell volume decrement and protected the CD95-expressing cells from apoptosis. A glutamine deprivation-dependent cell shrinkage with activation of the CD95-mediated pathway was also observed when asparaginase was added to the medium. Asparagine depletion had no role in this process. The cell-size shrinkage-dependent apoptosis induced by glutamine restriction in CD95-expressing leukemic cells may therefore be of clinical relevance in amidohydrolase enzyme therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Asparaginase / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Cell Membrane / metabolism
  • Cell Size
  • Clone Cells
  • Culture Media
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Glutamine / physiology*
  • HL-60 Cells
  • Humans
  • Kinetics
  • Leukemia, T-Cell / metabolism
  • Leukemia, T-Cell / pathology*
  • Membrane Glycoproteins / physiology
  • Mutation
  • Signal Transduction*
  • Tumor Cells, Cultured
  • fas Receptor / physiology*


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Carrier Proteins
  • Culture Media
  • FADD protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Membrane Glycoproteins
  • fas Receptor
  • Glutamine
  • Asparaginase