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

C. Fumarola, A. Zerbini, G. G. Guidotti

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1004-1013
Number of pages10
JournalCell Death and Differentiation
Issue number10
Publication statusPublished - 2001


  • Apoptosis
  • Asparaginase
  • CD95 (Fas/Apo-1) receptor
  • Cell-shrinkage
  • Glutamine

ASJC Scopus subject areas

  • Cell Biology


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