Exp Mol Med.  2010 May;42(5):395-405. 10.3858/emm.2010.42.5.041.

Chlorpromazine activates p21(Waf1/Cip1) gene transcription via early growth response-1 (Egr-1) in C6 glioma cells

Affiliations
  • 1Institute of Biomedical Science and Technology, Konkuk University Hospital, Seoul 143-729, Korea. yhlee58@konkuk.ac.kr
  • 2Department of Biomedical Science and Technology, Research Center for Transcription Control, Konkuk University, Seoul 143-701, Korea.
  • 3Department of Psychiatry, Clinical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 110-744, Korea.
  • 4Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Korea.

Abstract

2-Chloro-10-[3(-dimethylamino)propyl]phenothiazinemonohydrochloride (chlorpromazine) is a phenothiazine derivative used clinically to control psychotic disorders. It also exhibits an anticancer activity. Treatment with chlorpromazine (CPZ) results in cell-cycle arrest at the G2/M phase in rat C6 glioma cells. CPZ reduces the expression of cell cycle-related proteins, such as cyclin D1, cyclin A, and cyclin B1, but causes an increase in the p21(Waf1/Cip1) level. The molecular mechanism by which CPZ regulates p21(Waf1/Cip1) expression is unknown. Here, we provide evidence that CPZ activates the p21(Waf1/Cip1) gene promoter via induction of the transcription factor early growth response-1 (Egr-1) independently of p53 in C6 cells. A point mutation in the Egr-1-binding motif within the p21(Waf1/Cip1) promoter abrogated promoter inducibility due to CPZ. Forced expression of Egr-1 enhanced p21(Waf1/Cip1) promoter activity. In contrast, knockdown of endogenous Egr-1 by small interference RNA attenuated CPZ-induced p21(Waf1/Cip1) promoter activity. A chromatin immunoprecipitation assay demonstrated that Egr-1 binds to the p21(Waf1/Cip1) gene promoter. Further analysis showed that the ERK and JNK MAP kinases are required for induction of Egr-1 by CPZ. Finally, stable silencing of Egr-1 expression lead to attenuated CPZ-inducible p21(Waf1/Cip1) expression and inhibited G2/M phase cell-cycle arrest. These results demonstrate that a functional link between ERK and JNK MAP kinase pathways and p21(Waf1/Cip1) induction via Egr-1 contributes to CPZ-induced anticancer activity in C6 glioma cells.

Keyword

chlorpromazine; c-Jun N-terminal kinase; cyclin-dependent kinase inhibitor p21; early growth response-1; extracellular signal-regulated kinase; tumor suppressor protein p53
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