High levels of p110δ PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110δ inhibitors through PTEN activation.
FASEB J
; 26(6): 2498-508, 2012 Jun.
Article
em En
| MEDLINE
| ID: mdl-22391131
ABSTRACT
Class IA PI3K isoforms have divergent, nonredundant cell biological roles. In untransformed cells and tissues, p110α and p110ß are ubiquitously expressed, whereas p110δ expression is highly enriched in leukocytes. High levels of p110δ expression have been documented in some solid tumor cell lines, but the functional role is unknown. This study aimed to elucidate the link between elevated expression of p110δ PI3K and cancer. We report that in breast and prostate cancer cells that contain leukocyte levels of p110δ, p110δ activity dampens the activity of the PTEN tumor suppressor. Indeed, inactivation of p110δ in these cells led to PTEN activation, suppression of Akt phosphorylation, and inhibition of cell proliferation, with inhibition of PTEN activity being able to counterbalance p110δ inactivation. Likewise, forced overexpression of p110δ in cells with low p110δ expression reduced PTEN activity, resulting in increased Akt phosphorylation. Our data indicate that the oncogenic potential of p110δ PI3K overexpression might at least partially act through PTEN inactivation, and that p110δ-selective PI3K inhibitors can have a dual antitumor mechanism, namely by directly inhibiting p110δ signaling and by a broader inhibition of class I PI3K activity through PTEN activation. These data may have important implications in the intervention of breast cancer.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
PTEN Fosfo-Hidrolase
/
Classe Ia de Fosfatidilinositol 3-Quinase
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Grécia