Inhibition of Cell Proliferation and AP-1 Activity by Acrolein in Human A549 Lung Adenocarcinoma Cells Due to Thiol Imbalance and Covalent Modifications
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- 作者：Shyam Biswal ; George Acquaah-Mensah ; Kaushik Datta ; Xuli Wu ; and James P. Kehrer
- 刊名：Chemical Research in Toxicology
- 出版年：2002
- 出版时间：February 2002
- 年：2002
- 卷：15
- 期：2
- 页码：180 - 186
- 全文大小：127K
- 年卷期：v.15,no.2(February 2002)
- ISSN：1520-5010
文摘
Acrolein, a reactive 
,
-unsaturated aldehyde, is a common environmental pollutant, ametabolite 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 proliferationat nonlethal doses and may act through effects on redox-regulated transcription factors. Wepreviously reported that NF-
B activation is inhibited by acrolein in the A549 lung adenocarcinoma cell line in an IB-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 26and 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 sulfoximineto deplete glutathione to the same extent as seen with acrolein. c-jun antisense treatmentsdepressed c-jun protein below detectable levels at 4 h and inhibited cell proliferation (as assessedby [3H]thymidine incorporation) by 80%. Immunoprecipitation of c-jun protein after treatingA549 cells with acrolein revealed the presence of a lysine-acrolein adduct. There was, however,no effect of acrolein on c-jun N-terminal kinase activity or c-jun phosphorylation. These dataindicate that the inhibition of cell proliferation induced by acrolein correlates with the depletionof glutathione as well as the inhibition of AP-1 activation. AP-1 activation is likely affectedboth through changes in cellular thiol redox balance and by covalent modification of acroleinto c-jun, but not through effects on c-jun phosphorylation.
,-unsaturated aldehyde, is a common environmental pollutant, ametabolite 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 proliferationat nonlethal doses and may act through effects on redox-regulated transcription factors. Wepreviously reported that NF-B activation is inhibited by acrolein in the A549 lung adenocarcinoma cell line in an IB-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 26and 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 sulfoximineto deplete glutathione to the same extent as seen with acrolein. c-jun antisense treatmentsdepressed c-jun protein below detectable levels at 4 h and inhibited cell proliferation (as assessedby [3H]thymidine incorporation) by 80%. Immunoprecipitation of c-jun protein after treatingA549 cells with acrolein revealed the presence of a lysine-acrolein adduct. There was, however,no effect of acrolein on c-jun N-terminal kinase activity or c-jun phosphorylation. These dataindicate that the inhibition of cell proliferation induced by acrolein correlates with the depletionof glutathione as well as the inhibition of AP-1 activation. AP-1 activation is likely affectedboth through changes in cellular thiol redox balance and by covalent modification of acroleinto c-jun, but not through effects on c-jun phosphorylation.