Beta-carotene regulates NF-kappaB DNA-binding activity by a redox mechanism in human leukemia and colon adenocarcinoma cells.
We demonstrated previously that beta-carotene may affect cell growth by a redox mechanism. The purpose of this study was to determine whether the redox-sensitive transcription factor nuclear factor (NF)-kappaB may be involved in the growth-inhibitory and proapoptotic effects of the carotenoid. To test this hypothesis, human leukemic cells (HL-60) and colon adenocarcinoma cells (LS-174 and WiDr) were treated with beta-carotene, alone or in combination with alpha-tocopherol or N-acetylcysteine, and changes in 1) cell oxidative status, 2) cell growth and apoptosis, 3) DNA-binding activity of NF-kappaB and 4) expression of c-myc, a NF-kappaB target gene involved in apoptosis, were evaluated. In HL-60 cells, beta-carotene induced a significant increase in reactive oxygen species (ROS) production (P < 0.001) and in oxidized glutathione (GSSG) content (P < 0.005) at concentrations >/=10 micro mol/L. These effects were always accompanied by a sustained elevation of NF-kappaB and by a significant inhibition (P < 0.002) of cell growth. NF-kappaB DNA-binding activity increased at 3 h and persisted for at least 48 h. Colon adenocarcinoma cells displayed substantial differences in their sensitivity to beta-carotene, exhibiting increased ROS levels and activation of NF-kappaB at concentrations much lower in LS-174 cells (2.5-5.0 micro mol/L) than in WiDr cells (50-100 micro mol/L). In all cell lines studied, alpha-tocopherol and N-acetylcysteine inhibited the effects of beta-carotene on NF-kappaB, cell growth and apoptosis, and normalized the increased expression of c-myc induced by the carotenoid. These data suggest that the redox regulation of NF-kappaB induced by beta-carotene is involved in the growth-inhibitory and proapoptotic effects of the carotenoid in tumor cells.
Palozza
Paola
P
Institute of General Pathology, Catholic University, Rome, Italy. p.palozza@rm.inicatt.it
Serini
Simona
S
Torsello
Angela
A
Di Nicuolo
Fiorella
F
Piccioni
Elisabetta
E
Ubaldi
Vanessa
V
Pioli
Claudio
C
Wolf
Federica I
FI
Calviello
Gabriella
G
D000111:Acetylcysteine / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D016259:Genes, myc / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019207:beta Carotene / Q000378:metabolism / Q000502:physiology*
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019207:beta Carotene; D000111:Acetylcysteine