Polyamine depletion inhibits etoposide-induced NF-κB activation in transformed mouse fibroblasts

B. Tantini, C. Pignatti, M. Fattori, E. Fiumana, A. Facchini, C. Stefanelli, C. M. Caldarera, A. E. Pegg, F. Flamigni

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Abstract

In a previous research, we have shown that adequate levels of polyamines are required in transformed mouse fibroblasts for the correlated activations of MAPK subtypes (ERK and JNK) and caspases induced by etoposide and leading to apoptosis. We report now that the treatment of fibroblasts with etoposide also elicited a progressive and sustained increase of NF-κB activation. The DNA binding activity of p65 NF-κB subunit was increased up to approximately 4-fold and was accompanied by enhancement of p65 phosphorylation. A two days pre-treatment of fibroblasts with α-difluoromethylornithine (DFMO), which caused polyamine depletion, provoked a slight activating effect when given alone, but markedly inhibited the etoposide-induced increases in p65 DNA binding and phosphorylation. The NF-κB inhibiting effect of DFMO was prevented by the addition of exogenous putrescine, which restored the intracellular content of polyamines. Selective inhibitors of the etoposide-stimulated MAPK subtypes also reduced NF-κB activation. Moreover, pharmacological NF-κB inhibition reduced the increase in caspase activity and cell death elicited by etoposide, suggesting that NF-κB is involved in signaling to apoptosis. The results of the present study, together with our previous findings, suggest that polyamines play a permissive role in the pathways triggered by etoposide and leading to cell death of fibroblasts, by supporting the activation of MAPKs, NF-κB and caspases.

Original languageEnglish (US)
Pages (from-to)207-214
Number of pages8
JournalAmino Acids
Volume27
Issue number2
DOIs
Publication statusPublished - Oct 1 2004

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Tantini, B., Pignatti, C., Fattori, M., Fiumana, E., Facchini, A., Stefanelli, C., ... Flamigni, F. (2004). Polyamine depletion inhibits etoposide-induced NF-κB activation in transformed mouse fibroblasts. Amino Acids, 27(2), 207-214. https://doi.org/10.1007/s00726-004-0101-9