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

Pintus, Gianfranco and Tadolini, Bruna and Posadino, Anna Maria and Sanna, Bastiano and Debidda, Marcella and Bennardini, Federico and Sava, Gianni and Ventura, Carlo (2002) Inhibition of the MEK/ERK signaling pathway by the novel antimetastatic agent NAMI-A down regulates c-myc gene expression and endothelial cell proliferation. European Journal of Biochemistry, Vol. 269 (23), p. 5861-5870. eISSN 1432-1033. Article.

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DOI: 10.1046/j.1432-1033.2002.03307.x

Abstract

Imidazolium trans-imidazoledimethyl sulfoxide-tetrachlororuthenate (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) inhibitor PD98059, it completely counteracted PMA-induced ERK phosphorylation. Finally, NAMI-A and PD98059 down regulated c-myc gene expression to the same extent in serum-cultured cells and dose-dependently counteracted, and ultimately abolished, the increase in c-myc gene expression elicited by PMA in serum-free cells. These results suggest that inhibition of MEK/ERK signaling by NAMI-A may have an important role in modulating c-myc gene expression and ECV304 proliferation.

Item Type:Article
ID Code:1210
Status:Published
Refereed:Yes
Uncontrolled Keywords:Ruthenium compound, signal transduction, gene expression, cell proliferation, cancer
Subjects:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
001 Università di Sassari > 01 Dipartimenti > Scienze del farmaco
Publisher:Blackwell Science on behalf of the Federation of European Biochemical Societies / Wiley
eISSN:1432-1033
Copyright Holders:© 2002 FEBS
Deposited On:18 Aug 2009 10:04

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