Inhibition of HMC-1 mast cell proliferation by vitamin E: involvement of the protein kinase B pathway.
The effects of four natural tocopherols on the proliferation and signaling pathways were examined in the human mastocytoma cell line (HMC-1). The four tocopherols inhibited HMC-1 cell proliferation with different potency (delta > alpha = gamma > beta). Growth inhibition correlated with the reduction of PKB (protein kinase B) phosphorylation by the different tocopherols. The reduction of PKB phosphorylation led to a decrease of its activity, as judged from a parallel reduction of GSKalpha/beta phosphorylation. The translocation of PKB to the membrane, as a response to receptor stimulation by NGFbeta, is also prevented by treatment with tocopherols. In the presence of PKC or PP2A inhibitors, the reduction of PKB phosphorylation by tocopherols was still observed, thus excluding the direct involvement of these enzymes. Other pathways, such as the Ras-stimulated ERK1/2 (extracellular signal responsive kinase) pathway, were not affected by tocopherol treatment. The tocopherols did not significantly change oxidative stress in HMC-1 cells, suggesting that the observed effects are not the result of a general reduction of oxidative stress. Thus, the tocopherols interfere with PKB phosphorylation and reduce proliferation of HMC-1 cells, possibly by modulating either phosphatidylinositol 3-kinase, a kinase phosphorylating PKB (PDK1/2), or a phosphatase that dephosphorylates it. Inhibition of proliferation and PKB signaling in HMC-1 cells by vitamin E suggests a role in preventing diseases with mast cell involvement, such as allergies, atherosclerosis, and tumorigenesis.
Kempná
Petra
P
Institute of Biochemistry and Molecular Biology, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland.
Reiter
Elke
E
Arock
Michel
M
Azzi
Angelo
A
Zingg
Jean-Marc
JM
D017209:Apoptosis; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000166:cytology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D024505:Tocopherols / Q000378:metabolism / Q000494:pharmacology; D020298:U937 Cells; D014810:Vitamin E / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D024505:Tocopherols; D014810:Vitamin E; D018631:ras Proteins; C448021:glycogen synthase kinase 3 alpha