Reactive oxygen species from NAD(P)H:: quinone oxidoreductase constitutively activate NF-κB in malignant melanoma cells
Reactive oxygen species from NAD(P)H:: quinone oxidoreductase constitutively activate NF-κB in malignant melanoma cells
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DOI：
10.1152/ajpcell.2001.280.3.c659
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发表时间：
2001-03-01
影响因子：
5.5
通讯作者：
Hoidal, JR
中科院分区：
文献类型：
--
作者：
Brar, SS;Kennedy, TP;Hoidal, JR
转录因子核因子-kappaB(NF-kappaB)在恶性肿瘤中被结构性激活，其原因是核因子-kappaB抑制因子(I-kappaB)的活性增强，加速了I-kappaBα的降解。我们研究了氧化还原信号是否可能刺激这些事件。培养的黑色素瘤细胞在没有血清刺激的情况下产生超氧阴离子(O-2(-))。NAD(P)H：Q氧化还原酶(NQO)抑制剂Diumarol和Q类似物辣椒素可减少O-2(-)的产生，提示NQO通过Q介导的电子传递途径可能是肿瘤细胞内源性ROS的重要来源。用过氧化氢清除剂过氧化氢酶、巯基供体N-乙酰半胱氨酸、谷胱甘肽过氧化物酶类似物ebselen或Diumarol处理恶性黑色素瘤细胞会降低核因子-kappaB的活性。过氧化氢酶、N-乙酰半胱氨酸、ebselen、双酚A和辣椒素也抑制黑色素瘤和其他恶性细胞系的生长。这些结果提高了由NQO参与的内源性ROS机制能够以自分泌方式结构性地激活NF-kappaB的可能性，并暗示了新的抗氧化剂策略的可能性，以阻断黑色素瘤细胞生长的氧化信号。
The transcription factor nuclear factor-kappaB (NF-kappaB) is constitutively activated in malignancies from enhanced activity of inhibitor of NF-kappaB (I kappaB) kinase, with accelerated I kappaB alpha 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 H2O2 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.