Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells

Soon Young Shin, Byeong Hyeok Choi, Jesang Ko, Se Hyun Kim, Yong Sik Kim, Young Han Lee

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Clozapine (CZP), a dibenzodiazepine derivative with a piperazinyl side chain, is in clinical use as an antipsychotic drug. This study investigated the effect of CZP on the modulation of the PI3K/Akt/GSK-3β pathway in PTEN-negative U-87MG glioblastoma cells. Treatment with CZP rapidly inhibited the basal and EGF-induced phosphorylation of Akt. The inhibition of Akt resulted in the dephosphorylation of GSK-3β and increased GSK-3β kinase activity. A voltage-sensitive Ca2+ channel blocker and calmodulin (CaM) antagonists inhibited Akt phosphorylation, whereas elevation of the intracellular Ca2+ concentration prevented CZP-induced dephosphorylation of Akt and GSK-3β, suggesting that Ca2+/CaM participates in the inhibition of Akt by CZP in U-87MG cells. In addition, similar to LY294002, CZP arrested cell cycle progression at G0/G1 phase, which was accompanied by decreased expression of cyclin D1. The reduction in the cyclin D1 level induced by CZP was abrogated by the inhibition of GSK-3β, the inhibition of proteasome-dependent proteolysis, or an increase in the intracellular Ca2+ concentration. These results suggest that the antipsychotic drug CZP modulates the PI3K/Akt/GSK-3β pathway by counteracting Ca2+/CaM in PTEN-negative U-87MG glioblastoma cells.

Original languageEnglish
Pages (from-to)1876-1886
Number of pages11
JournalCellular Signalling
Volume18
Issue number11
DOIs
Publication statusPublished - 2006 Nov

Keywords

  • Akt
  • Calmodulin antagonist
  • Cell cycle
  • Clozapine
  • Cyclin D1
  • U-87MG glioblastoma

ASJC Scopus subject areas

  • Cell Biology

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