Vascular endothelial growth factor A, secreted in response to transforming growth factor-ß1 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells.
Asian J Androl
; 14(5): 745-51, 2012 Sep.
Article
em En
| MEDLINE
| ID: mdl-22705563
ABSTRACT
Hypoxia and transforming growth factor-ß1 (TGF-ß1) increase vascular endothelial growth factor A (VEGFA) expression in a number of malignancies. This effect of hypoxia and TGF-ß1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-ß1 was shown to induce VEGFA(165) secretion from both normal cell lines (HPV7 and RWPE1) and prostate cancer cell lines (DU145 and PC3). Conversely, hypoxia-stimulated VEGFA(165) secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-ß1 expression in PC3 prostate cancer cells, and the TGF-ß type I receptor (ALK5) kinase inhibitor partially blocked hypoxia-mediated VEGFA(165) secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor (VEGFR) 1 (Flt-1) and 2 (Flk-1/KDR). Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA(165) treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA(165) was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-ß1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-ß1 and hypoxia on metastatic prostate cancers.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Hipóxia Celular
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Fator A de Crescimento do Endotélio Vascular
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Fator de Crescimento Transformador beta1
Limite:
Humans
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Male
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article