Protein kinase C-alpha-mediated regulation of low-density lipoprotein receptor related protein and urokinase increases astrocytoma invasion.
Cancer Res
; 67(21): 10241-51, 2007 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-17974965
ABSTRACT
Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor-related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-alpha (PKC-alpha) phosphorylated and down-regulated LRP expression. Pretreatment of tumor cells with PKC inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, PKC-alpha small interfering RNA (siRNA), and short hairpin RNA abrogated phorbol 12-myristate 13-acetate-induced down-regulation of LRP and inhibited astrocytic tumor invasion in vitro. In xenograft glioblastoma mouse model and in vitro transmembrane invasion assay, LRP-deficient cells, which secreted high levels of urokinase-type plasminogen activator (uPA), invaded extensively the surrounding normal brain tissue, whereas the LRP-overexpressing and uPA-deficient cells did not invade into the surrounding normal brain. siRNA, targeted against uPA in LRP-deficient clones, attenuated their invasive potential. Taken together, our results strongly suggest the involvement of PKC-alpha/PI3K signaling pathways in the regulation of LRP-mediated astrocytoma invasion. Thus, a strategy of combining small molecule inhibitors of PKC-alpha and PI3K could provide a new treatment paradigm for glioblastomas.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Astrocitoma
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Ativador de Plasminogênio Tipo Uroquinase
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Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade
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Proteína Quinase C-alfa
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos