Caspase activation in etoposide‐treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion

FEBS Letters

Fattori, Monia²  Pignatti, Carla²  Flamigni, Flavio²  Caldarera, Claudio M²  Tantini, Benedetta²  Clo, Carlo¹  Pegg, Anthony E³  Stefanelli, Claudio²  Guarnieri, Carlo²  Stanic’, Ivana²  Mackintosh, Caroline A³ 

[1]Institute of Biological Chemistry, University of Parma, 43100 Parma, Italy

[2]Department of Biochemistry ‘G. Moruzzi’, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy

[3]Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Centre, Hershey, PA 17033, USA

关键词: Apoptosis;    Caspase;    Extracellular signal-regulated kinase;    c-Jun NH2-terminal kinase;    Polyamines;    Ornithine decarboxylase;    MAPK;    mitogen-activated protein kinase;    ERK;    extracellular signal-regulated kinase;    JNK;    c-Jun NH2-terminal kinase;    AcDEVD-AMC;    acetyl-Asp-Glu-Val-Asp-amino-4-methylcoumarin;    AcDEVD-CHO;    acetyl-Asp-Glu-Val-Asp-aldehyde;    DFMO;    α-difluoromethylornithine;    NF-κB;    nuclear factor-κB;    ODC;    ornithine decarboxylase;   

DOI  :  10.1016/S0014-5793(02)03242-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Activation of the extracellular signal-regulated kinases (ERKs) 1 and 2 is correlated to cell survival, but in some cases ERKs can act in signal transduction pathways leading to apoptosis. Treatment of mouse fibroblasts with 20 μM etoposide elicited a sustained phosphorylation of ERK 1/2, that increased until 24 h from the treatment in parallel with caspase activity. The inhibitor of ERK activation PD98059 abolished caspase activation, but caspase inhibition did not reduce ERK 1/2 phosphorylation, suggesting that ERK activation is placed upstream of caspases. Both ERK and caspase activation were blocked in cells depleted of polyamines by the ornithine decarboxylase inhibitor α-difluoromethylornithine (DFMO). In etoposide-treated cells, DFMO also abolished phosphorylation of c-Jun NH₂-terminal kinases triggered by the drug. Polyamine replenishment with exogenous putrescine restored the ability of the cells to undergo caspase activation and ERK 1/2 phosphorylation in response to etoposide. Ornithine decarboxylase activity decreased after etoposide, indicating that DFMO exerts its effect by depleting cellular polyamines before induction of apoptosis. These results reveal a role for polyamines in the transduction of the death signal triggered by etoposide.

【 授权许可】

Unknown