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

Claudio Stefanelli, Benedetta Tantini, Monia Fattori, Ivana Stanic', Carla Pignatti, Carlo Clo, Carlo Guarnieri, Claudio M. Caldarera, Caroline A. Mackintosh, Anthony Pegg, Flavio Flamigni

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-228
Number of pages6
JournalFEBS Letters
Volume527
Issue number1-3
DOIs
StatePublished - Sep 11 2002

Fingerprint

Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Polyamines
Etoposide
Fibroblasts
Caspases
Mitogen-Activated Protein Kinase 3
Chemical activation
Mitogen-Activated Protein Kinase 1
Eflornithine
Signal Transduction
Cells
Apoptosis
Signal transduction
Ornithine Decarboxylase
Putrescine
JNK Mitogen-Activated Protein Kinases
Cell Survival
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Stefanelli, Claudio ; Tantini, Benedetta ; Fattori, Monia ; Stanic', Ivana ; Pignatti, Carla ; Clo, Carlo ; Guarnieri, Carlo ; Caldarera, Claudio M. ; Mackintosh, Caroline A. ; Pegg, Anthony ; Flamigni, Flavio. / Caspase activation in etoposide-treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion. In: FEBS Letters. 2002 ; Vol. 527, No. 1-3. pp. 223-228.
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abstract = "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.",
author = "Claudio Stefanelli and Benedetta Tantini and Monia Fattori and Ivana Stanic' and Carla Pignatti and Carlo Clo and Carlo Guarnieri and Caldarera, {Claudio M.} and Mackintosh, {Caroline A.} and Anthony Pegg and Flavio Flamigni",
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Stefanelli, C, Tantini, B, Fattori, M, Stanic', I, Pignatti, C, Clo, C, Guarnieri, C, Caldarera, CM, Mackintosh, CA, Pegg, A & Flamigni, F 2002, 'Caspase activation in etoposide-treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion', FEBS Letters, vol. 527, no. 1-3, pp. 223-228. https://doi.org/10.1016/S0014-5793(02)03242-8

Caspase activation in etoposide-treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion. / Stefanelli, Claudio; Tantini, Benedetta; Fattori, Monia; Stanic', Ivana; Pignatti, Carla; Clo, Carlo; Guarnieri, Carlo; Caldarera, Claudio M.; Mackintosh, Caroline A.; Pegg, Anthony; Flamigni, Flavio.

In: FEBS Letters, Vol. 527, No. 1-3, 11.09.2002, p. 223-228.

Research output: Contribution to journalArticle

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T1 - Caspase activation in etoposide-treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion

AU - Stefanelli, Claudio

AU - Tantini, Benedetta

AU - Fattori, Monia

AU - Stanic', Ivana

AU - Pignatti, Carla

AU - Clo, Carlo

AU - Guarnieri, Carlo

AU - Caldarera, Claudio M.

AU - Mackintosh, Caroline A.

AU - Pegg, Anthony

AU - Flamigni, Flavio

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Y1 - 2002/9/11

N2 - 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.

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