[HTML][HTML] Identifying inhibitors of epithelial-mesenchymal transition by connectivity map–based systems approach
AK Reka, R Kuick, H Kurapati, TJ Standiford… - Journal of Thoracic …, 2011 - Elsevier
Journal of Thoracic Oncology, 2011•Elsevier
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-β (TGF-β)-induced EMT, we identified potential EMT
inhibitors. We used a publicly available database (www. broad. mit. edu/cmap) comprising …
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-β (TGF-β)-induced EMT, we identified potential EMT
inhibitors. We used a publicly available database (www. broad. mit. edu/cmap) comprising …
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-β (TGF-β)-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-β signaling along with 17-AAG, a known modulator of TGF-β 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-β 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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