Excess putrescine accumulation inhibits the formation of modified eukaryotic initiation factor 5A (eIF-5A) and induces apoptosis.
DH23A cells, an alpha-difluoromethylornithine-resistant variant of the parental hepatoma tissue culture cells, express high levels of stable ornithine decarboxylase. Aberrantly high expression of ornithine decarboxylase results in a large accumulation of endogenous putrescine and increased apoptosis in DH23A cells when alpha-difluoromethylornithine is removed from the culture. Treatment of DH23A cells with exogenous putrescine in the presence of alpha-difluoromethylornithine mimics the effect of drug removal, suggesting that putrescine is a causative agent or trigger of apoptosis. Accumulation of excess intracellular putrescine inhibits the formation of hypusine in vivo, a reaction that proceeds by the transfer of the butylamine moiety of spermidine to a lysine residue in eukaryotic initiation factor 5A (eIF-5A). Treatment of DH23A cells with diaminoheptane, a competitive inhibitor of the post-translational modification of eIF-5A, causes both the suppression of eIF-5A modification in vivo and induction of apoptosis. These data support the hypothesis that rapid degradation of ornithine decarboxylase is a protective mechanism to avoid cell toxicity from putrescine accumulation. Further, these data suggest that suppression of modified eIF-5A formation is one mechanism by which cells may be induced to undergo apoptosis.
Tome
M E
ME
Department of Radiation Oncology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ 85724, USA.
Fiser
S M
SM
Payne
C M
CM
Gerner
E W
EW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008854:Microscopy, Electron; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D011073:Polyamines / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011700:Putrescine / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D000097574:Eukaryotic Translation Initiation Factor 5A
D003959:Diamines; D000518:Eflornithine; D004791:Enzyme Inhibitors; D008239:Lysine; D009955:Ornithine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D010448:Peptide Initiation Factors; D011073:Polyamines; D011700:Putrescine; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine; C015127:1,7-diaminoheptane