Inhibition of cell proliferation and AP-1 activity by acrolein in human A549 lung adenocarcinoma cells due to thiol imbalance and covalent modifications

Shyam Biswal, George Acquaah-Mensah, Kaushik Datta, Xuli Wu, James P. Kehrer

Research output: Contribution to journalArticle

Abstract

Acrolein, a reactive α,β-unsaturated aldehyde, is a common environmental pollutant, a metabolite of the anticancer drug cyclophosphamide, and a byproduct of lipid peroxidation. An increase in acrolein production has been proposed as a marker for Alzheimer's disease, diabetic glomerular lesions, and atherosclerosis. Acrolein is a potent inhibitor of cell proliferation at nonlethal doses and may act through effects on redox-regulated transcription factors. We previously reported that NF-κB activation is inhibited by acrolein in the A549 lung adenocarcinoma cell line in an IκB-independent manner [Horton et al. (1999) J. Biol. Chem. 274, 9200-9206]. The current data demonstrate that AP-1 activation in A549 cells is decreased by 26 and 50% at 0.5 and 1 h, respectively, after exposure to 50 fmol/cell (a nonlethal dose) of acrolein. Inhibition of AP-1 activation also occurred following treatment with buthionine sulfoximine to deplete glutathione to the same extent as seen with acrolein, c-jun antisense treatments depressed c-jun protein below detectable levels at 4 h and inhibited cell proliferation (as assessed by [3H]thymidine incorporation) by 80%. Immunoprecipitation of c-jun protein after treating A549 cells with acrolein revealed the presence ofa lysine - acrolein adduct. There was, however, no effect of acrolein on c-jun N-terminal kinase activity or c-jun phosphorylation. These data indicate that the inhibition of cell proliferation induced by acrolein correlates with the depletion of glutathione as well as the inhibition of AP-1 activation. AP-1 activation is likely affected both through changes in cellular thiol redox balance and by covalent modification of acrolein to c-jun, but not through effects on c-jun phosphorylation.

Original languageEnglish (US)
Pages (from-to)180-186
Number of pages7
JournalChemical research in toxicology
Volume15
Issue number2
DOIs
StatePublished - Mar 4 2002

ASJC Scopus subject areas

  • Toxicology

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