Putrescine activates oxidative stress dependent apoptotic death in ornithine decarboxylase overproducing mouse myeloma cells.
Accumulation of putrescine in ornithine decarboxylase overproducing cells provokes apoptotic death that is inhibited by 2-difluoromethylornithine, a specific inhibitor of ODC. The apoptotic process provoked by putrescine involves the release of cytochrome c from the mitochondria and activation of caspases cascades demonstrated by the cleavage of caspase-2, polyA-ribose polymerase (PARP), and proteolytic cleavage of the translation initiation factor 4G (eIF4G). The general caspases inhibitor BD-fmk inhibits PARP cleavage but not cell death. Aminoguanidine, an inhibitor of amine oxidases, inhibits the cleavage of PARP and cell death, whereas the antioxidant BHA inhibits PARP cleavage but not cell death. The intracellular Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA/AM) inhibits both PARP cleavage and cell death. Although the ability of BAPTA/AM to inhibit the induction of apoptosis may suggest that the accumulating putrescine stimulates the release of Ca2+, such a Ca2+ elevation was not observed. We suggest that the accumulation of putrescine leads to oxidative stress that causes cell death.
Erez
Omri
O
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Goldstaub
Dan
D
Friedman
Joseph
J
Kahana
Chaim
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D053143:Caspase 2; D020169:Caspases / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009101:Multiple Myeloma / Q000201:enzymology / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011700:Putrescine / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D002614:Chelating Agents; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D006146:Guanidines; D011073:Polyamines; D004533:Egtazic Acid; D020122:tert-Butylhydroperoxide; D019001:Nitric Oxide Synthase; D011065:Poly(ADP-ribose) Polymerases; D053143:Caspase 2; D020169:Caspases; D009955:Ornithine Decarboxylase; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C004479:pimagedine; D002118:Calcium; D011700:Putrescine