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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-? (TGF-?)-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-? signaling along with 17-AAG, a known modulator of TGF-? 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-? 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.
SUBMITTER: Reka AK
PROVIDER: S-EPMC3196823 | biostudies-literature | 2011 Nov
REPOSITORIES: biostudies-literature
Reka Ajaya Kumar AK Kuick Rork R Kurapati Himabindu H Standiford Theodore J TJ Omenn Gilbert S GS Keshamouni Venkateshwar G VG
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20111101 11
<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]