Enhanced invasion of Tax-expressing fibroblasts into the basement membrane is repressed by phosphorylated ascorbate with simultaneous decreases in intracellular oxidative stress and NF-kappa B activation.
Invasion of rat fibroblastic cells Rat-1 through Matrigel was shown to be promoted by transfection with tax gene of human T-cell leukemia virus type 1. We found that an oxidation-resistant type of vitamin C (Asc), Asc-2-O-phosphate (Asc2P), inhibited the invasion of the tax-transfected Rat-1 cells (W4 cells). Intracellular Asc (Ascin), after enzymatic dephosphorylation of administered Asc2P, was more abundant in W4 cells than in Rat-1 cells, and the ratio of dehydroascorbic acid versus Asc was increased in W4 cells but scarcely in Rat-1 cells, according to the enhanced level of intracellular reactive oxygen species (ROSin) in W4 cells. Asc2P notably repressed the increases in both ROSin and secretion of matrix metalloproteases (MMPs), but did not affect Tax protein expression in tax-transfectants. NF-kappa B activation, as evidenced by its translocation to the nucleus in W4 cells, was also repressed by Asc2P. Thus, the tax-promoted invasion together with the enhanced production of MMPs occurred with NF-kappa B activation and the increase in ROSin, both of which were effectively reduced by Asc2P. These findings indicate the therapeutic efficacy of Ascin-enriching agents for the prevention against tumor invasion in which ROSin plays a major role.
Nagao
N
N
Department of Cell Biochemistry, Hiroshima Prefectural University School of BioSciences, Hiroshima 727-0023, Japan.
Etoh
T
T
Yamaoka
S
S
Okamoto
T
T
Miwa
N
N
D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001485:Basement Membrane / Q000166:cytology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016356:Gene Products, tax / Q000235:genetics*; D016355:Genes, pX; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D014162:Transfection
D016356:Gene Products, tax; D016328:NF-kappa B; C011669:ascorbate-2-phosphate; D001205:Ascorbic Acid