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 language | English |
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Pages (from-to) | 1876-1886 |
Number of pages | 11 |
Journal | Cellular Signalling |
Volume | 18 |
Issue number | 11 |
DOIs | |
Publication status | Published - 2006 Nov |
Keywords
- Akt
- Calmodulin antagonist
- Cell cycle
- Clozapine
- Cyclin D1
- U-87MG glioblastoma
ASJC Scopus subject areas
- Cell Biology