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NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth.


ABSTRACT: Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.

SUBMITTER: Stepulak A 

PROVIDER: S-EPMC1266139 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

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NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth.

Stepulak Andrzej A   Sifringer Marco M   Rzeski Wojciech W   Endesfelder Stefanie S   Gratopp Alexander A   Pohl Elena E EE   Bittigau Petra P   Felderhoff-Mueser Ursula U   Kaindl Angela M AM   Bührer Christoph C   Hansen Henrik H HH   Stryjecka-Zimmer Marta M   Turski Lechoslaw L   Ikonomidou Chrysanthy C  

Proceedings of the National Academy of Sciences of the United States of America 20051017 43


Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression  ...[more]

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