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 |
|---|---|
| Pages (from-to) | 1876-1886 |
| Number of pages | 11 |
| Journal | Cellular Signalling |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2006 Nov 1 |
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Keywords
- Akt
- Calmodulin antagonist
- Cell cycle
- Clozapine
- Cyclin D1
- U-87MG glioblastoma
ASJC Scopus subject areas
- Cell Biology
Cite this
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, Je Sang; Kim, Se Hyun; Kim, Yong Sik; Lee, Young Han.
In: Cellular Signalling, Vol. 18, No. 11, 01.11.2006, p. 1876-1886.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells
AU - Shin, Soon Young
AU - Choi, Byeong Hyeok
AU - Ko, Je Sang
AU - Kim, Se Hyun
AU - Kim, Yong Sik
AU - Lee, Young Han
PY - 2006/11/1
Y1 - 2006/11/1
N2 - 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.
AB - 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.
KW - Akt
KW - Calmodulin antagonist
KW - Cell cycle
KW - Clozapine
KW - Cyclin D1
KW - U-87MG glioblastoma
UR - http://www.scopus.com/inward/record.url?scp=33749253862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749253862&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2006.02.004
DO - 10.1016/j.cellsig.2006.02.004
M3 - Article
C2 - 16542821
AN - SCOPUS:33749253862
VL - 18
SP - 1876
EP - 1886
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
IS - 11
ER -