Mechanism of cancer cell adaptation to metabolic stress: proteomics identification of a novel thyroid hormone-mediated gastric carcinogenic signaling pathway.
Mol Cell Proteomics
; 8(1): 70-85, 2009 Jan.
Article
em En
| MEDLINE
| ID: mdl-18723843
ABSTRACT
Gastric cancer is the second most common cancer worldwide and has a poor prognosis. To determine the mechanism of adaptation to metabolic stress in cancer cells, we used gastric cancer as a model system to reveal the potential signaling pathways involved. Two-dimensional polyacrylamide gel electrophoresis coupled with ESI-Q-TOF MS/MS analysis was used to identify differentially expressed proteins between gastric tumor tissues and the corresponding noncancerous tissues. In total, 107 spots with significant alteration (+/-over 2-fold, p < 0.05) were positively identified by MS/MS analysis. Altered expression of representative proteins was validated by RT-PCR and Western blotting. Cluster analysis of the changed proteins revealed an interesting group of metabolic proteins, which suggested accumulation of triiodothyronine (T(3); the major functional component of thyroid hormone) and overexpression of hypoxia-induced factor (HIF) in gastric carcinoma. These observations were further confirmed by electrochemiluminescence immunoassay and immunohistochemistry. T(3)-induced expression of HIF1-alpha and vascular endothelial growth factor was further verified using a gastric cancer cell line and in vivo mouse model. Because the early accumulation of HIF1-alpha was found to be independent of de novo transcription, we also found that the cytosolic cascade phosphatidylinositol 3-kinase/Akt pathway sensitive to T(3) stimulus was involved. Furthermore we demonstrated that T(3)-induced overexpression of HIF1-alpha was mediated by fumarate accumulation and could be enhanced by fumarate hydratase inactivation but inhibited by 2-oxoglutarate. These results provide evidence for alteration of metabolic proteins and dysfunction of thyroid hormone regulation in gastric tumors, and a novel thyroid hormone-mediated tumorigenic signaling pathway is proposed. Our findings are considered a significant step toward a better understanding of adaptations to metabolic stress in gastric carcinogenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
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Estresse Fisiológico
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Hormônios Tireóideos
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Adaptação Fisiológica
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Transdução de Sinais
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Proteômica
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article