Antioxidants tiron and N-acetyl-L-cysteine differentially mediate apoptosis in melanoma cells via a reactive oxygen species-independent NF-kappaB pathway.
Tiron and N-acetyl-L-cysteine (NAC) have been recognized as potential antioxidants capable of inhibiting apoptosis induced by reactive oxygen species (ROS). Although the ROS-scavenging function of tiron and NAC is clear, the mechanism for their regulation of apoptosis is still elusive. Here we demonstrate that tiron increases nuclear factor-kappaB (NF-kappaB)/DNA binding and as a result enhances NF-kappaB transcriptional activity. In contrast, NAC inhibits NF-kappaB activation by reducing inhibitor of kappaB kinase (IKK) activity. Moreover, the expression of an NF-kappaB target gene, the chemokine CXCL1, is promoted by tiron and suppressed by NAC. Finally, tiron confers an antiapoptotic function, while NAC imparts a proapoptotic function in melanoma cells. These functions correlate with the alteration of mitochondrial membrane potential but not ROS production or induction of activating protein-1 (AP-1). This study underscores the potential benefits of regulating NF-kappaB activity in melanoma cells as a therapeutic approach.
Yang
Jinming
J
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Su
Yingjun
Y
Richmond
Ann
A
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology*; D000111:Acetylcysteine / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D009336:Necrosis; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000975:Antioxidants; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D000111:Acetylcysteine