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.
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: Rebecca S Muraoka; Nancy Dumont; Christoph A Ritter; Teresa C Dugger; Dana M Brantley; Jin Chen; Evangeline Easterly; L Renee Roebuck; Sarah Ryan; Philip J Gotwals; Victor Koteliansky; Carlos L Arteaga Journal: J Clin Invest Date: 2002-06 Impact factor: 14.808
Authors: Ajaya Kumar Reka; Guoan Chen; Richard C Jones; Ravi Amunugama; Sinae Kim; Alla Karnovsky; Theodore J Standiford; David G Beer; Gilbert S Omenn; Venkateshwar G Keshamouni Journal: Carcinogenesis Date: 2014-02-07 Impact factor: 4.944
Authors: Tong Liu; Hao Zhang; Li Sun; Danyu Zhao; Peng Liu; Meisi Yan; Neeha Zaidi; Sudeh Izadmehr; Animesh Gupta; Wahid Abu-Amer; Minna Luo; Jie Yang; Xunyan Ou; Yining Wang; Xuefeng Bai; Yan Wang; Maria I New; Mone Zaidi; Tony Yuen; Caigang Liu Journal: Proc Natl Acad Sci U S A Date: 2017-07-03 Impact factor: 11.205