Arsenic trioxide represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloid leukemia, HL-60.
It has been proposed that eukaryotic nuclear factor nuclear factor kappa-B (NF-kappaB) and cyclooxygenase-2 (COX-2) are implicated in the pathogenesis of many human diseases including cancer. Arsenic has been widely used in medicine in Oriental countries. Recent studies have shown that arsenic trioxide (As(2)O(3)) could induce in vitro growth inhibition and apoptosis of malignant lymphocytes, and myeloma cells. However, the molecular mechanisms by which As(2)O(3) initiates cellular signaling toward cell death are still unclear. In the present study, the effects of As(2)O(3) on NF-kappaB and COX-2 expression in HL-60 cells were investigated. As(2)O(3) suppressed DNA-binding activity of NF-kappaB composed of p65/p50 heterodimer through preventing the degradation of IkappaB-alpha and the nuclear translocation of p65 subsequently as well as interrupting the binding of NF-kappaB with their consensus sequences. Inhibitory effect of As(2)O(3) on NF-kappaB DNA activity was dependent upon intracellular glutathione (GSH) and H(2)O(2) level, but not superoxide anion. Futhermore, we found that As(2)O(3) also downregulated the expression of COX-2, which has NF-kappaB binding site on its promoter through repressing the NF-kappaB DNA-binding activity.
Han
Seong-Su
SS
Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Kim
Kihyun
K
Hahm
Eun-Ryeong
ER
Park
Chan H
CH
Kimler
Bruce F
BF
Lee
Sook J
SJ
Lee
Se-Hoon
SH
Kim
Won S
WS
Jung
Chul Won
CW
Park
Keunchil
K
Kim
Jingook
J
Yoon
Sung-Soo
SS
Lee
Je-Ho
JH
Park
Seyeon
S
D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051550:I-kappa B Kinase; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects
D001152:Arsenicals; D008565:Membrane Proteins; D016328:NF-kappa B; D010087:Oxides; D021122:Protein Subunits; D004247:DNA; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D005978:Glutathione; D000077237:Arsenic Trioxide