Polyamine depletion induces apoptosis through mitochondria-mediated pathway.
Polyamines, namely putrescine, spermidine, and spermine, are essential for cell survival and proliferation. A decrease in intracellular polyamine levels is associated with apoptosis. In this study, we used inhibitors of polyamine biosynthesis to examine the effect of polyamine depletion. A combination of inhibitors of ornithine decarboxylase, S-adenosylmethionine decarboxylase, or spermidine synthase decreased intracellular polyamine levels and induced cell death in a WEHI231 murine B cell line. These cells exhibited apoptotic features including chromatin condensation and oligonucleosomal DNA fragmentation. Addition of exogenous polyamines reversed the observed features of apoptotic cell death. Similar effects were also observed in other cell lines: a human B cell line Ramos and a human T cell line Jurkat. Depletion of polyamines induced activation of caspase-3 and disruption of the mitochondrial membrane potential (Delta psi m). Inhibition of caspase activities by an inhibitor prevented the apoptotic nuclear changes but not Delta psi m disruption induced by polyamine depletion. Overexpression of Bcl-xl, an anti-apoptotic Bcl-2 family protein, completely inhibited Delta psi m disruption, caspase activation, and cell death. These results indicate that the depletion of intracellular polyamines triggers the mitochondria-mediated pathway for apoptosis, resulting in caspase activation and apoptotic cell death.
Nitta
Takeshi
T
Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Igarashi
Kazuei
K
Yamamoto
Naoki
N
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008928:Mitochondria / Q000502:physiology*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011436:Spermidine Synthase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D012437:Adenosylmethionine Decarboxylase