Identifying inhibitors of epithelial-mesenchymal transition by connectivity map-based systems approach.
J Thorac Oncol
; 6(11): 1784-92, 2011 Nov.
Article
em En
| MEDLINE
| ID: mdl-21964532
ABSTRACT
BACKGROUND:
Acquisition of mesenchymal phenotype by epithelial cells by means of epithelial-mesenchymal transition (EMT) is considered as an early event in the multistep process of tumor metastasis. Therefore, inhibition of EMT might be a rational strategy to prevent metastasis.METHODS:
Using the global gene expression profile from a cell culture model of transforming growth factor-ß (TGF-ß)-induced EMT, we identified potential EMT inhibitors. We used a publicly available database (www.broad.mit.edu/cmap) comprising gene expression profiles obtained from multiple different cell lines in response to various drugs to derive negative correlations to EMT gene expression profile using Connectivity Map, a pattern matching tool.RESULTS:
Experimental validation of the identified compounds showed rapamycin as a novel inhibitor of TGF-ß signaling along with 17-AAG, a known modulator of TGF-ß pathway. Both of these compounds completely blocked EMT and the associated migratory and invasive phenotype. The other identified compound, LY294002, demonstrated a selective inhibition of mesenchymal markers, cell migration and invasion, without affecting the loss of E-cadherin expression or Smad phosphorylation.CONCLUSIONS:
Our data reveal that rapamycin is a novel modulator of TGF-ß signaling, and along with 17-AAG and LY294002, could be used as therapeutic agent for inhibiting EMT. This study demonstrates the potential of a systems approach in identifying novel modulators of a complex biological process.
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Base de dados:
MEDLINE
Assunto principal:
Adenocarcinoma
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Movimento Celular
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Benzoquinonas
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Fator de Crescimento Transformador beta
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Adenocarcinoma Bronquioloalveolar
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Lactamas Macrocíclicas
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Inibidores Enzimáticos
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Transição Epitelial-Mesenquimal
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Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article