S-Space College of Medicine/School of Medicine (의과대학/대학원) Psychiatry (정신과학전공) Journal Papers (저널논문_정신과학전공)
Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells
- Shin, Soon Young; Choi, Byeong Hyeok; Ko, Jesang; Kim, Se Hyun; Kim, Yong Sik; Lee, Young Han
- Issue Date
- Cell Signal. 2006 Nov;18(11):1876-86. Epub 2006 Mar 6.
- Antipsychotic Agents/pharmacology; Calcium/*metabolism; Calmodulin/*metabolism; Cell Line, Tumor; Clozapine/*pharmacology; Cytoskeletal Proteins/metabolism; Gene Deletion; Glioblastoma/drug therapy/genetics/*metabolism; Humans; Nuclear Proteins/metabolism; PTEN Phosphohydrolase/genetics; Phosphorylation; Proto-Oncogene Proteins c-akt/*antagonists & inhibitors; Signal Transduction; Tumor Cells, Cultured
- 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-3beta 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-3beta and increased GSK-3beta kinase activity. A voltage-sensitive Ca(2+) channel blocker and calmodulin (CaM) antagonists inhibited Akt phosphorylation, whereas elevation of the intracellular Ca(2+) concentration prevented CZP-induced dephosphorylation of Akt and GSK-3beta, suggesting that Ca(2+)/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-3beta, the inhibition of proteasome-dependent proteolysis, or an increase in the intracellular Ca(2+) concentration. These results suggest that the antipsychotic drug CZP modulates the PI3K/Akt/GSK-3beta pathway by counteracting Ca(2+)/CaM in PTEN-negative U-87MG glioblastoma cells.
- 0898-6568 (Print)
- Files in This Item: There are no files associated with this item.