Potential inhibition of PDK1/Akt signaling by phenothiazines suppresses cancer cell proliferation and survival.
Ann N Y Acad Sci
; 1138: 393-403, 2008 Sep.
Article
en En
| MEDLINE
| ID: mdl-18837915
3'-Phosphoinositide-dependent kinase-1 (PDK1) has been identified for its ability to phosphorylate and activate Akt. Accumulated studies have shown that the activation of the PDK1/Akt pathway plays a pivotal role in cell survival, proliferation, and tumorigenesis. Therefore, the PDK1/Akt pathway is believed to be a critical target for cancer intervention. In this paper, we report the discovery of a new function of phenothiazines, widely known as antipsychotics, inhibiting PDK1/Akt pathway. Upon epidermal growth factor (EGF) stimulation, phenothiazines specifically suppressed the kinase activity of PDK1 and the phosphorylation level of Akt. The inhibition of PDK1/Akt kinase resulted in suppression of EGF-induced cell growth and induction of apoptosis in human ovary cancer cells. In particular, phenothiazines were highly selective for downstream targets of PDK1/Akt and did not inhibit the activation of phosphatidylinositol 3-kinase (PI3K), EGFR, or extracellular signal-regulated kinase 1/2 (ERK1/2). In particular, phenothiazines effectively suppressed tumor growth in nude mice of human cancer cells. Taken together, these findings provide strong evidence for novel function of phenothiazines, pharmacologically targeting PDK1/Akt for anticancer drug discovery.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenotiazinas
/
Transducción de Señal
/
Supervivencia Celular
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Proteínas Serina-Treonina Quinasas
/
Proliferación Celular
/
Proteínas Proto-Oncogénicas c-akt
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Ann N Y Acad Sci
Año:
2008
Tipo del documento:
Article
Pais de publicación:
Estados Unidos