Publications
Detailed Information
Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells
Cited 37 time in
Web of Science
Cited 40 time in Scopus
- Authors
- Issue Date
- 2006-03-18
- Publisher
- Elsevier
- Citation
- Cell Signal. 2006 Nov;18(11):1876-86. Epub 2006 Mar 6.
- Keywords
- 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
- 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
https://hdl.handle.net/10371/22107
- Files in This Item:
- There are no files associated with this item.
- Appears in Collections:
Item View & Download Count
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.