Glutamine deprivation-mediated cell shrinkage induces ligand-independent CD95 receptor signaling and apoptosis.
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.
Fumarola
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Department of Experimental Medicine, Section of Immunology and Molecular Pathology, University of Parma, 43100 Parma, Italy.
Zerbini
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A
Guidotti
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GG
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001215:Asparaginase / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D048429:Cell Size; D002999:Clone Cells; D003470:Culture Media; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D005973:Glutamine / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology; D009154:Mutation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D003470:Culture Media; C505533:FADD protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D005973:Glutamine; D001215:Asparaginase