title: Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity by genistein, a tyrosine kinase inhibitor.
abstract: The effects of the protein tyrosine kinase inhibitor genistein on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in monkey kidney epithelial CV-1 cells were determined. CV-1 cells were pretreated with genistein for 2 hr before treatment with 100 nM TPA. ODC activity was determined 9 hr after TPA treatment. Genistein inhibited TPA-induced ODC activity at 0.1, 1, 10, 25, 50, 100, 200, and 400 microM by 0%, 0%, 42%, 59%, 62%, 81%, 91%, and 100%, respectively (IC50 = 20 microM). Genistein inhibited TPA-induced mitogen-activated protein kinase (MAPK) tyrosine phosphorylation and the accumulation of steady state levels of ODC mRNA at 400 microM but not at 25 microM. Genistein, at 25 microM, did not alter the TPA-induced phosphorylation of p90 ribosomal S6 kinase but caused a approximately 50% decrease of the TPA-induced phosphorylation of p70 S6 kinase (p70S6K), a protein kinase involved in the control of translational efficiency. Taken together, these data indicate that genistein may inhibit TPA-induced ODC activity at the transcriptional and translational levels through the inhibition of MAPK and p70S6K activation, respectively. The regulation of MAPK and p70S6K may be mediated through different protein tyrosine kinases that have differential sensitivity to genistein.
authors.affiliation: Department of Human Oncology, Medical School, University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Tseng
authors.forename: A K
authors.initials: AK
authors.lastname: Verma
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein; D000882:Haplorhini; D007529:Isoflavones / Q000494:pharmacology*; D009955:Ornithine Decarboxylase / Q000235:genetics; D065108:Ornithine Decarboxylase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000032:analysis; D019893:Ribosomal Protein S6 Kinases; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007529:Isoflavones; D065108:Ornithine Decarboxylase Inhibitors; D012333:RNA, Messenger; D014443:Tyrosine; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate