Pleckstrin-2-promoted PPM1B degradation plays an important role in transforming growth factor-ß-induced breast cancer cell invasion and metastasis.
Cancer Sci
; 114(6): 2429-2444, 2023 Jun.
Article
em En
| MEDLINE
| ID: mdl-36928924
ABSTRACT
Transforming growth factor-ß (TGF-ß) is known to promote breast cancer cell migration, invasion, and dissemination; however, the underlying molecular mechanisms are not yet well characterized. Here, we report that TGF-ß induces pleckstrin-2 (PLEK2) expression by Smad3 and signal transducer and activator of transcription 3 (STAT3) activating PLEK2 promoter activity. Higher PLEK2 expression is associated with poor prognosis in breast cancer patients. Overexpression and knockout experiments in MDA-MB-231 and MCF-7 breast cancer cells revealed that PLEK2 promotes cell migration, invasion, and dissemination in 2D and 3D cell culture. Moreover, PLEK2 promotes metastasis of breast cancer cells in vivo. Pleckstrin-2 localizes to the cell membrane and cell protrusions following TGF-ß treatment. Furthermore, inhibition of PI3K phosphorylation abolishes TGF-ß- and PLEK2-induced cell invasion. The carboxyl-terminal PH domain of PLEK2 is critical for TGF-ß- and PLEK2-induced Akt activation and plays an important role in cell invasion. Pleckstrin-2 interacts with PPM1B and promotes its ubiquitin-dependent degradation. The PLEK2-PPM1B axis utilizes nuclear factor-κB signaling to promote cell migration and invasion. Our data implicate the TGF-ß-STAT3/Smad3-PLEK2-PPM1B signaling cascade in TGF-ß-induced breast cancer cell migration and invasion. These findings suggest that PLEK2/PPM1B could represent novel targets for the intervention of breast cancer metastasis.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Fator de Crescimento Transformador beta
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Cancer Sci
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China