Activation of heat shock factor 1 by pyrrolidine dithiocarbamate is mediated by its activities as pro-oxidant and thiol modulator.
Pyrrolidine dithiocarbamate (PDTC) is known to inhibit NF-kappa B, which plays a critical role(s) as an immediate early mediator of immune and inflammatory responses. Here we show that PDTC induces heat shock factor 1 (HSF1) activation and heat shock protein expression, while other antioxidants such as butylated hydroxytoluene (BHT), n-propylgallate (PG), ascorbic acid (AA), and N-acetyl-L-cysteine (NAC) do not. Since PDTC exerts other functions than antioxidant, e.g., a pro-oxidant, metal chelator, and thiol group modulator, we examined which of these activities is responsible for the PDTC-induced HSF1 activation. PDTC-induced HSF1 activation was not prevented by metal chelators, EDTAs, indicating that the metal chelating effect of PDTC is not linked to the HSF1 activation. PDTC increased intracellular GSSG level. In addition, PDTC-induced activation of HSF1 was significantly inhibited by NAC and a thiol-reducing agent dithiothreitol (DTT), while it was partially prevented by other antioxidants, AA, BHT, and PG. These results suggest that the activation of HSF1 by PDTC may be due to its activities as pro-oxidant and thiol group modulator rather than anti-oxidant.
Kim
S H
SH
Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea.
Han
S I
SI
Oh
S Y
SY
Chung
H Y
HY
Kim
H D
HD
Kang
H S
HS
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019803:Glutathione Disulfide / Q000187:drug effects / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D011435:Propyl Gallate / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology*; D014157:Transcription Factors
D000975:Antioxidants; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D016877:Oxidants; D011759:Pyrrolidines; D013438:Sulfhydryl Compounds; D013859:Thiocarbamates; D014157:Transcription Factors; D002084:Butylated Hydroxytoluene; C020972:pyrrolidine dithiocarbamic acid; D011435:Propyl Gallate; D001205:Ascorbic Acid; D019803:Glutathione Disulfide; D000111:Acetylcysteine