tailieunhanh - Báo cáo Y học: Inhibition of the MEK/ERK signaling pathway by the novel antimetastatic agent NAMI-A down regulates c-myc gene expression and endothelial cell proliferation

Imidazolium trans-imidazoledimethyl sulfoxide-tetrachlo-roruthenate (NAMI-A) is a novel ruthenium-containing experimental antimetastatic agent. Compelling evidence ascribes apivotal role toendothelial cells in theorchestration of tumor angiogenesis and metastatic growth, suggesting antiangiogenic therapy as an attractive approach for anticancer treatment. In this context, activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway has been found fundamental in transducing extracellular stimuli that modulate a number of cellular process including cell prolif-eration, migration and invasion | Eur. J. Biochem. 269 5861-5870 2002 FEBS 2002 doi Inhibition of the MEK ERK signaling pathway by the novel antimetastatic agent NAMI-A down regulates c-myc gene expression and endothelial cell proliferation Gianfranco Pintus1 2 Bruna Tadolini1 2. Anna Maria Posadino1 2 Bastiano Sanna1 2. Marcella Debidda1 2 Federico Bennardini2 3 Gianni Sava4 and Carlo Ventura1 2 1Department of Biomedical Sciences Division of Biochemistry Laboratory of Cardiovascular Research 2Division of Cell Biology National Institute of Biostructures and Biosystems and 3Department of Drug Sciences University of Sassari Italy 4Callerio Foundation Institutes for Biological Research Trieste Italy Imidazolium irans-imidazoledimethyl sulfoxide-tetrachlo-roruthenate NAMI-A is a novel ruthenium-containing experimental antimetastatic agent. Compelling evidence ascribes a pivotal role to endothelial cells in the orchestration of tumor angiogenesis and metastatic growth suggesting antiangiogenic therapy as an attractive approach for anticancer treatment. In this context activation of the mitogen-activated protein kinase MAPK extracellular signal-regulated kinase ERK signaling pathway has been found fundamental in transducing extracellular stimuli that modulate a number of cellular process including cell proliferation migration and invasion. Here we show that exposure of the transformed endothelial cell line ECV304 to NAMI-A significantly inhibited DNA synthesis as well as the expression of the proliferating cell nuclear antigene PCNA . These responses were associated with a marked down-regulation of ERK phosphorylation in serum-cultured cells. In addition NAMI-A markedly reduced serum stimulated- and completely suppressed phorbol 12-myristate 13-acetate PMA -triggered MAPK ERK kinase activity. NAMI-A was also able to inhibit the phosphorylation of MEK the upstream activator of ERK and similar to both the protein kinase C PKC inhibitor GF109203X and the MAPK ERK MEK .

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