Excess putrescine accumulation inhibits the formation of modified eukaryotic initiation factor 5A (eIF-5A) and induces apoptosis

• Published in: Biochemical journal 1997-12, Vol.328 ( Pt 3) (3), p.847-854
• Main Authors: Tome, M E, Fiser, S M, Payne, C M, Gerner, E W
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Cell Division - drug effects; Diamines - pharmacology; Eflornithine - pharmacology; Enzyme Inhibitors - pharmacology; Eukaryotic Translation Initiation Factor 5A; Lysine - analogs & derivatives; Lysine - metabolism; Microscopy, Electron; Ornithine Decarboxylase - metabolism; Ornithine Decarboxylase Inhibitors; Peptide Initiation Factors - genetics; Peptide Initiation Factors - metabolism; Polyamines - metabolism; Protein Processing, Post-Translational; Putrescine - metabolism; Putrescine - pharmacology; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Tumor Cells, Cultured
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/bj3280847

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.