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A Central Role for JNK/AP-1 Pathway in the Pro-Oxidant Effect of Pyrrolidine Dithiocarbamate through Superoxide Dismutase 1 Gene Repression and Reactive Oxygen Species Generation in Hematopoietic Human Cancer Cell Line U937.
PLoS One. 2015; 10(5):e0127571.Plos

Abstract

Pyrrolidine dithiocarbamate (PDTC) known as antioxidant and specific inhibitor of NF-κB was also described as pro-oxidant by inducing cell death and reactive oxygen species (ROS) accumulation in cancer. However, the mechanism by which PDTC indices its pro-oxidant effect is unknown. Therefore, we aimed to evaluate the effect of PDTC on the human Cu/Zn superoxide dismutase 1 (SOD1) gene transcription in hematopoietic human cancer cell line U937. We herein show for the first time that PDTC decreases SOD1 transcripts, protein and promoter activity. Furthermore, SOD1 repression by PDTC was associated with an increase in oxidative stress as evidenced by ROS production. Electrophoretic mobility-shift assays (EMSA) show that PDTC increased binding of activating protein-1 (AP-1) in dose dependent-manner suggesting that the MAPkinase up-stream of AP-1 is involved. Ectopic NF-κB p65 subunit overexpression had no effect on SOD1 transcription. In contrast, in the presence of JNK inhibitor (SP600125), p65 induced a marked increase of SOD1 promoter, suggesting that JNK pathway is up-stream of NF-κB signaling and controls negatively its activity. Indeed, using JNK deficient cells, PDTC effect was not observed nether on SOD1 transcription or enzymatic activity, nor on ROS production. Finally, PDTC represses SOD1 in U937 cells through JNK/c-Jun phosphorylation. Taken together, these results suggest that PDTC acts as pro-oxidant compound in JNK/AP-1 dependent-manner by repressing the superoxide dismutase 1 gene leading to intracellular ROS accumulation.

Authors+Show Affiliations

Unidad de Reumatología, Nivel plaza del Instituto Autónomo Hospital Universitario de Los Andes. Mérida, Venezuela.INSERM U1029, Laboratoire de l'Angiogenèse et du Microenvironnement des Cancers, Pessac, France.UMR 8601, Laboratoire de Chimie & Biochimie Pharmacologique, Paris, France.INSERM U1029, Laboratoire de l'Angiogenèse et du Microenvironnement des Cancers, Pessac, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25996379

Citation

Riera, Humberto, et al. "A Central Role for JNK/AP-1 Pathway in the Pro-Oxidant Effect of Pyrrolidine Dithiocarbamate Through Superoxide Dismutase 1 Gene Repression and Reactive Oxygen Species Generation in Hematopoietic Human Cancer Cell Line U937." PloS One, vol. 10, no. 5, 2015, pp. e0127571.
Riera H, Afonso V, Collin P, et al. A Central Role for JNK/AP-1 Pathway in the Pro-Oxidant Effect of Pyrrolidine Dithiocarbamate through Superoxide Dismutase 1 Gene Repression and Reactive Oxygen Species Generation in Hematopoietic Human Cancer Cell Line U937. PLoS One. 2015;10(5):e0127571.
Riera, H., Afonso, V., Collin, P., & Lomri, A. (2015). A Central Role for JNK/AP-1 Pathway in the Pro-Oxidant Effect of Pyrrolidine Dithiocarbamate through Superoxide Dismutase 1 Gene Repression and Reactive Oxygen Species Generation in Hematopoietic Human Cancer Cell Line U937. PloS One, 10(5), e0127571. https://doi.org/10.1371/journal.pone.0127571
Riera H, et al. A Central Role for JNK/AP-1 Pathway in the Pro-Oxidant Effect of Pyrrolidine Dithiocarbamate Through Superoxide Dismutase 1 Gene Repression and Reactive Oxygen Species Generation in Hematopoietic Human Cancer Cell Line U937. PLoS One. 2015;10(5):e0127571. PubMed PMID: 25996379.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Central Role for JNK/AP-1 Pathway in the Pro-Oxidant Effect of Pyrrolidine Dithiocarbamate through Superoxide Dismutase 1 Gene Repression and Reactive Oxygen Species Generation in Hematopoietic Human Cancer Cell Line U937. AU - Riera,Humberto, AU - Afonso,Valéry, AU - Collin,Pascal, AU - Lomri,Abderrahim, Y1 - 2015/05/21/ PY - 2015/02/06/received PY - 2015/04/16/accepted PY - 2015/5/22/entrez PY - 2015/5/23/pubmed PY - 2016/3/5/medline SP - e0127571 EP - e0127571 JF - PloS one JO - PLoS One VL - 10 IS - 5 N2 - Pyrrolidine dithiocarbamate (PDTC) known as antioxidant and specific inhibitor of NF-κB was also described as pro-oxidant by inducing cell death and reactive oxygen species (ROS) accumulation in cancer. However, the mechanism by which PDTC indices its pro-oxidant effect is unknown. Therefore, we aimed to evaluate the effect of PDTC on the human Cu/Zn superoxide dismutase 1 (SOD1) gene transcription in hematopoietic human cancer cell line U937. We herein show for the first time that PDTC decreases SOD1 transcripts, protein and promoter activity. Furthermore, SOD1 repression by PDTC was associated with an increase in oxidative stress as evidenced by ROS production. Electrophoretic mobility-shift assays (EMSA) show that PDTC increased binding of activating protein-1 (AP-1) in dose dependent-manner suggesting that the MAPkinase up-stream of AP-1 is involved. Ectopic NF-κB p65 subunit overexpression had no effect on SOD1 transcription. In contrast, in the presence of JNK inhibitor (SP600125), p65 induced a marked increase of SOD1 promoter, suggesting that JNK pathway is up-stream of NF-κB signaling and controls negatively its activity. Indeed, using JNK deficient cells, PDTC effect was not observed nether on SOD1 transcription or enzymatic activity, nor on ROS production. Finally, PDTC represses SOD1 in U937 cells through JNK/c-Jun phosphorylation. Taken together, these results suggest that PDTC acts as pro-oxidant compound in JNK/AP-1 dependent-manner by repressing the superoxide dismutase 1 gene leading to intracellular ROS accumulation. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/25996379/A_Central_Role_for_JNK/AP_1_Pathway_in_the_Pro_Oxidant_Effect_of_Pyrrolidine_Dithiocarbamate_through_Superoxide_Dismutase_1_Gene_Repression_and_Reactive_Oxygen_Species_Generation_in_Hematopoietic_Human_Cancer_Cell_Line_U937_ L2 - https://dx.plos.org/10.1371/journal.pone.0127571 DB - PRIME DP - Unbound Medicine ER -