Protein kinase C (PKC)-delta/-epsilon mediate the PKC/Akt-dependent phosphorylation of extracellular signal-regulated kinases 1 and 2 in MCF-7 cells stimulated by bradykinin.
In this paper the signal transduction pathways evoked by bradykinin (BK) in MCF-7 breast cancer cells were investigated. BK activation of the B(2) receptor provoked: (a) the phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2); (b) the translocation from the cytosol to the membrane of the conventional protein kinase C-alpha (PKC-alpha) and novel PKC-delta and PKC-epsilon; (c) the phosphorylation of protein kinase B (PKB/ Akt); (d) the proliferation of MCF-7 cells. The BK-induced ERK1/2 phosphorylation was completely blocked by PD98059 (an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK)) and by LY294002 (an inhibitor of phosphoinositide 3-kinase (PI3K)), and was reduced by GF109203X (an inhibitor of both novel and conventional PKCs); Gö6976, a conventional PKCs inhibitor, did not have any effect. The BK-induced phosphorylation of PKB/Akt was blocked by LY294002 but not by PD98059. Furthermore, LY294002 inhibited the BK-provoked translocation of PKC-delta and PKC-epsilon suggesting that PI3K may be upstream to PKCs. Finally, the proliferative effects of BK were blocked by PD98059, GF109203X and LY294002. These observations demonstrate that BK acts as a proliferative agent in MCF-7 cells activating intracellular pathways involving novel PKC-delta/-epsilon, PKB/Akt and ERK1/2.
Greco
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S
Laboratory of Cellular Physiology, Department of Biological and Environmental Sciences and Technologies, DiSTeBA, Ecotekne, Via Provinciale per Monteroni, 73100 Lecce, Italy.
Storelli
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C
Marsigliante
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S
D000704:Analysis of Variance; D001692:Biological Transport; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D001943:Breast Neoplasms / Q000201:enzymology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D007609:Kallidin / Q000031:analogs & derivatives / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D013268:Stimulation, Chemical; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D002867:Chromones; D004963:Estrenes; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011760:Pyrrolidinones; D044005:Tetrahydroisoquinolines; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C054550:bradykinin, (hydroxy-Pro)(3)-Lys-; C076640:bradykinin, Hyp(3)-Thi(5)-Tic(7)-Oic(8)-desArg(9)-; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007609:Kallidin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C070515:bisindolylmaleimide I; D001920:Bradykinin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one