title: Identifying inhibitors of epithelial-mesenchymal transition by connectivity map-based systems approach.
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-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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Ajaya Kumar
authors.initials: AK
authors.lastname: Reka
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.forename: Himabindu
authors.initials: H
authors.lastname: Kurapati
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Gilbert S
authors.initials: GS
authors.lastname: Omenn
authors.forename: Venkateshwar G
authors.initials: VG
authors.lastname: Keshamouni
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016227:Benzoquinones / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D016227:Benzoquinones; D014408:Biomarkers, Tumor; D015820:Cadherins; D002867:Chromones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D047029:Lactams, Macrocyclic; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C112765:tanespimycin; D020123:Sirolimus