Reactive oxygen species from NAD(P)H:quinone oxidoreductase constitutively activate NF-kappaB in malignant melanoma cells.
The transcription factor nuclear factor-kappaB (NF-kappaB) is constitutively activated in malignancies from enhanced activity of inhibitor of NF-kappaB (IkappaB) kinase, with accelerated IkappaBalpha degradation. We studied whether redox signaling might stimulate these events. Cultured melanoma cells generated superoxide anions (O(2)(-)) without serum stimulation. O(2)(-) generation was reduced by the NAD(P)H:quinone oxidoreductase (NQO) inhibitor dicumarol and the quinone analog capsaicin, suggesting that electron transfer from NQO through a quinone-mediated pathway may be an important source of endogenous reactive oxygen species (ROS) in tumor cells. Treatment of malignant melanoma cells with the H(2)O(2) scavenger catalase, the sulfhydryl donor N-acetylcysteine, the glutathione peroxidase mimetic ebselen, or dicumarol decreased NF-kappaB activation. Catalase, N-acetylcysteine, ebselen, dicumarol, and capsaicin also inhibited growth of melanoma and other malignant cell lines. These results raise the possibility that ROS produced endogenously by mechanisms involving NQO can constitutively activate NF-kappaB in an autocrine fashion and suggest the potential for new antioxidant strategies for interruption of oxidant signaling of melanoma cell growth.
Brar
S S
SS
Departments of Internal Medicine and the Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina 28232, USA.
Kennedy
T P
TP
Whorton
A R
AR
Sturrock
A B
AB
Huecksteadt
T P
TP
Ghio
A J
AJ
Hoidal
J R
JR
D000975:Antioxidants / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009249:NADP / Q000502:physiology; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology*; D011003:Ploidies; D017382:Reactive Oxygen Species / Q000502:physiology*; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D009249:NADP; D001728:Dicumarol; D009247:NADH, NADPH Oxidoreductases; C072396:NAD(P)H plastoquinone oxidoreductase; D002211:Capsaicin