Ascochlorin inhibits growth factor-induced HIF-1α activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells.
J Cell Biochem
; 113(4): 1302-13, 2012 Apr.
Article
em En
| MEDLINE
| ID: mdl-22109717
ABSTRACT
Ascochlorin, a non-toxic prenylphenol compound derived from the fungus Ascochyta viciae, has been shown recently to have anti-cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti-cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)-induced HIF-1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF-1α expression in response to EGF stimulation, but not in response to hypoxia (1% O(2)) or treatment with a transition metal (CoCl(2)). Second, ascochlorin inhibited EGF-induced ERK-1/2 activation but not AKT activation, both of which play essential roles in EGF-induced HIF-1α protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR-specific small interfering RNA (siRNA) diminished HIF-1α expression, which suggested that ascochlorin inhibits HIF-1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF-mediated induction of HIF-1α expression in CaSki cells, providing a potentially new avenue of development of anti-cancer drugs that target tumor angiogenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenóis
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Transdução de Sinais
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Neoplasias do Colo do Útero
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Proteínas Quinases S6 Ribossômicas 70-kDa
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Fator A de Crescimento do Endotélio Vascular
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MAP Quinases Reguladas por Sinal Extracelular
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Alcenos
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Receptores ErbB
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article