EMAIL THIS PAGE TO A FRIEND

PloS one

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.


PMID 25996379

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.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

SAB4504451
Anti-phospho-c-Jun (pSer243) antibody produced in rabbit, affinity isolated antibody
J2128 Anti-phospho-c-Jun (pSer63) antibody produced in rabbit, affinity isolated antibody, buffered aqueous glycerol solution
SAB4504368
Anti-phospho-c-Jun (pSer63) antibody produced in rabbit, affinity isolated antibody
J2253 Anti-phospho-c-Jun (pSer73) antibody produced in rabbit, affinity isolated antibody, buffered aqueous glycerol solution
SAB4504369
Anti-phospho-c-Jun (pSer73) antibody produced in rabbit, affinity isolated antibody
SAB4504452
Anti-phospho-c-Jun (pThr239) antibody produced in rabbit, affinity isolated antibody
SAB4504453
Anti-phospho-c-Jun (pThr91) antibody produced in rabbit, affinity isolated antibody
SAB4504454
Anti-phospho-c-Jun (pThr93) antibody produced in rabbit, affinity isolated antibody
SAB4504455
Anti-phospho-c-Jun (pTyr170) antibody produced in rabbit, affinity isolated antibody
SAB4300015
Anti-phospho-JUN (pSer243) antibody produced in rabbit, affinity isolated antibody
SAB4300002
Anti-phospho-JUN (pSer73) antibody produced in rabbit, affinity isolated antibody
SAB4300014
Anti-phospho-JUN (pThr239) antibody produced in rabbit, affinity isolated antibody
SAB4300011
Anti-phospho-JUN (pThr91) antibody produced in rabbit, affinity isolated antibody
SAB4300012
Anti-phospho-JUN (pThr93) antibody produced in rabbit, affinity isolated antibody
SAB4300013
Anti-phospho-JUN (pTyr170) antibody produced in rabbit, affinity isolated antibody
SAB4300198
Anti-phospho-MAPK9 (pThr183) antibody produced in rabbit, affinity isolated antibody
J4399 Monoclonal Anti-phospho-c-Jun (pThr91,93) antibody produced in mouse, ~2 mg/mL, clone C-J 4C4/1, purified immunoglobulin, buffered aqueous solution