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

Title
Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells
Author
이영한
Keywords
Akt; calmodulin antagonist; cell cycle; clozapine; cyclin D1; U-87MG glioblastoma
Issue Date
2006-11
Publisher
ELSEVIER SCIENCE INC
Citation
CELLULAR SIGNALLING, v. 18, No. 11, Page. 1876-1886
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-3 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-3 beta and increased GSK-3 beta 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-3 beta 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-3 beta, 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-3 beta pathway by counteracting Ca2+/CaM in PTEN-negative U-87MG glioblastoma cells, (c) 2006 Elsevier Inc. All rights reserved.
URI
https://www.sciencedirect.com/science/article/pii/S0898656806000404https://repository.hanyang.ac.kr/handle/20.500.11754/108876
ISSN
0898-6568; 1873-3913
DOI
10.1016/j.cellsig.2006.02.004
Appears in Collections:
COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > ETC
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