Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C.
The effect of alpha-tocopherol (vitamin E) on the proliferation of vascular smooth muscle cells (A7r5), human osteosarcoma cells (Saos-2), fibroblasts (Balb/3T3), and neuroblastoma cells (NB2A) has been studied. The proliferation of vascular smooth muscle cells was inhibited by physiologically relevant concentrations of alpha-tocopherol, neuroblastoma cells were only sensitive to higher alpha-tocopherol concentrations, and proliferation of the other cell lines was not inhibited. The inhibition of smooth muscle cell proliferation was specific for alpha-tocopherol. Trolox, phytol, and alpha-tocopherol esters had no effect. Proliferation of smooth muscle cells stimulated by platelet-derived growth factor or endothelin was completely sensitive to alpha-tocopherol. If smooth muscle cells were stimulated by fetal calf serum, proliferation was 50% inhibited by alpha-tocopherol. No effect of alpha-tocopherol was observed when proliferation of smooth muscle cells was stimulated by bombesin and lysophosphatidic acid. The possibility of an involvement of protein kinase C in the cell response to alpha-tocopherol was suggested by experiments with the isolated enzyme and supported by the 2- to 3-fold stimulation of phorbol ester binding induced by alpha-tocopherol in sensitive cells. Moreover, alpha-tocopherol also caused inhibition of protein kinase C translocation induced by phorbol esters and inhibition of the phosphorylation of its 80-kDa protein substrate in smooth muscle cells. A model is discussed by which alpha-tocopherol inhibits cell proliferation by interacting with the cytosolic protein kinase C, thus preventing its membrane translocation and activation.
Boscoboinik
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Institut für Biochemie und Molekularbiologie, Universität Bern, Switzerland.
Szewczyk
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A
Hensey
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C
Azzi
A
A
D000818:Animals; D015153:Blotting, Western; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D002458:Cell Fractionation; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D004072:Digitonin / Q000494:pharmacology; D051379:Mice; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D014810:Vitamin E / Q000494:pharmacology*
D002839:Chromans; D010703:Phorbol Esters; D014810:Vitamin E; D002084:Butylated Hydroxytoluene; D004247:DNA; D011493:Protein Kinase C; D004072:Digitonin; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid