An NAD(P)H oxidase regulates growth and transcription in melanoma cells

被引:135
作者
Brar, SS
Kennedy, TP
Sturrock, AB
Huecksteadt, TP
Quinn, MT
Whorton, AR
Hoidal, JR
机构
[1] Carolinas Med Ctr, Dept Internal Med, Charlotte, NC 28232 USA
[2] Carolinas Med Ctr, Canon Res Ctr, Charlotte, NC 28232 USA
[3] Univ Utah, Dept Internal Med, Div Resp Crit Care & Occupat Pulm Med, Salt Lake City, UT 84132 USA
[4] Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA
[5] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2002年 / 282卷 / 06期
关键词
superoxide anion; diphenylene iodonium; p22(phox); gp91(phox); p67(phox); NOX1; NOX4; nuclear factor-kappa B; cAMP response; element; dicumarol;
D O I
10.1152/ajpcell.00496.2001
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Malignant melanoma cells spontaneously generate reactive oxygen species (ROS) that promote constitutive activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Although antioxidants and inhibitors of NAD(P)H oxidases significantly reduce constitutive NF-kappaB activation and suppress cell proliferation (11), the nature of the enzyme responsible for ROS production in melanoma cells has not been determined. To address this issue, we now have characterized the source of ROS production in melanoma cells. We report that ROS are generated by isolated, cytosol-free melanoma plasma membranes, with inhibition by NAD( P) H oxidase inhibitors. The p22(phox), gp91(phox), and p67(phox) components of the human phagocyte NAD(P)H oxidase and the gp91(phox) homolog NOX4 were demonstrated in melanomas by RT-PCR and sequencing, and protein product for both p22(phox) and gp91(phox) was detected in cell membranes by immunoassay. Normal human epidermal melanocytes expressed only p22(phox) and NOX4. Melanoma proliferation was reduced by NAD( P) H oxidase inhibitors and by transfection of antisense but not sense oligonucleotides for p22(phox) and NOX4. Also, the flavoprotein inhibitor diphenylene iodonium inhibited constitutive DNA binding of nuclear protein to the NF-kappaB and cAMP-response element consensus oligonucleotides, without affecting DNA binding activity to activator protein-1 or OCT-1. This suggests that ROS generated in autocrine fashion by an NAD( P) H oxidase may play a role in signaling malignant melanoma growth.
引用
收藏
页码:C1212 / C1224
页数:13
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