Vitamin C is a kinase inhibitor: dehydroascorbic acid inhibits IkappaBalpha kinase beta.
Reactive oxygen species (ROS) are key intermediates in cellular signal transduction pathways whose function may be counterbalanced by antioxidants. Acting as an antioxidant, ascorbic acid (AA) donates two electrons and becomes oxidized to dehydroascorbic acid (DHA). We discovered that DHA directly inhibits IkappaBalpha kinase beta (IKKbeta) and IKKalpha enzymatic activity in vitro, whereas AA did not have this effect. When cells were loaded with AA and induced to generate DHA by oxidative stress in cells expressing a constitutive active IKKbeta, NF-kappaB activation was inhibited. Our results identify a dual molecular action of vitamin C in signal transduction and provide a direct linkage between the redox state of vitamin C and NF-kappaB signaling events. AA quenches ROS intermediates involved in the activation of NF-kappaB and is oxidized to DHA, which directly inhibits IKKbeta and IKKalpha enzymatic activity. These findings define a function for vitamin C in signal transduction other than as an antioxidant and mechanistically illuminate how vitamin C down-modulates NF-kappaB signaling.
Cárcamo
Juan M
JM
Program in Molecular Pharmacology and Chemistry, Box 451, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Pedraza
Alicia
A
Bórquez-Ojeda
Oriana
O
Zhang
Bing
B
Sanchez
Roberto
R
Golde
David W
DW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D003683:Dehydroascorbic Acid / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014162:Transfection
D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D004247:DNA; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D001205:Ascorbic Acid; D010100:Oxygen; D003683:Dehydroascorbic Acid