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Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF‐κb, and MAP kinases
Author(s) -
Chung Kwang Chul,
Park Jae Hyun,
Kim Chul Hoon,
Lee Hyun Woo,
Sato Noboru,
Uchiyama Yasuo,
Ahn Young Soo
Publication year - 2000
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(20000101)59:1<117::aid-jnr14>3.0.co;2-q
Subject(s) - pyrrolidine dithiocarbamate , viability assay , glutathione , kinase , p38 mitogen activated protein kinases , mapk/erk pathway , chemistry , microbiology and biotechnology , nf κb , biochemistry , biology , signal transduction , cell , enzyme
Nuclear factor κB (NF‐κB) is a transcription factor involved in the expression of a wide range of genes, most of which code for proteins that play a role in immunity and inflammation. Pyrrolidine dithiocarbamate (PDTC) is a well‐known inhibitor of NF‐κB. Although its mechanism of action is conferred by its antioxidant property, other mechanisms by which PDTC can act as a prooxidant, metal chelator, and free thiol group modulator have recently been suggested. Here we report that PDTC caused a dual effect on cell viability in neuronal rat pheochromocytoma (PC12) cells, depending on its concentration. Increase of intracellular zinc and copper ion levels selectively potentiated the cytotoxic PDTC effect in a dose‐dependent manner, and thiol reagents, such as glutathione and N‐acetylcysteine, as well as divalent metal‐chelating reagents, such as EDTA and bathocuproline disulfonic acid, blocked its cell death effect. The differential effect of PDTC on cell viability correlates well with the inhibition of NF‐κB activities. In addition, PDTC differentially activated microtubule‐associated protein (MAP) kinases, such as extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK), but not p38, depending on its dose, and the coaddition of glutathione (GSH), other antioxidants, and metal ions also modulated their activities. Furthermore, stable Bcl‐2 expression blocked the PDTC‐induced cell death. These results suggest that the thiol groups and free zinc and copper ion levels are important for the novel biphasic PDTC effect on cell viability, which is associated with the differential activation of NF‐κB and MAP kinases. J. Neurosci. Res. 59:117–125, 2000 © 2000 Wiley‐Liss, Inc.