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

Cited 29 time in Web of Science Cited 31 time in Scopus
Authors
Shin, Soon Young; Choi, Byeong Hyeok; Ko, Jesang; Kim, Se Hyun; Kim, Yong Sik; Lee, Young Han
Issue Date
2006-03-18
Publisher
Elsevier
Citation
Cell Signal. 2006 Nov;18(11):1876-86. Epub 2006 Mar 6.
Keywords
Antipsychotic Agents/pharmacologyCalcium/*metabolismCalmodulin/*metabolismCell Line, TumorClozapine/*pharmacologyCytoskeletal Proteins/metabolismGene DeletionGlioblastoma/drug therapy/genetics/*metabolismHumansNuclear Proteins/metabolismPTEN Phosphohydrolase/geneticsPhosphorylationProto-Oncogene Proteins c-akt/*antagonists & inhibitorsSignal TransductionTumor Cells, Cultured
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-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.
ISSN
0898-6568 (Print)
Language
English
URI
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2M-4JDN6F4-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=596260bb3181c322ff2d35b249c5fd5f

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16542821

http://hdl.handle.net/10371/22107
DOI
https://doi.org/10.1016/j.cellsig.2006.02.004
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College of Medicine/School of Medicine (의과대학/대학원)Psychiatry (정신과학전공)Journal Papers (저널논문_정신과학전공)
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