Identifying Inhibitors of Epithelial-mesenchymal Transition by Connectivity Map-based Systems Approach

Overview

Journal J Thorac Oncol

Publisher Elsevier

Specialties Oncology
Pulmonary Medicine

Date 2011 Oct 4

PMID 21964532

Citations 29

Authors

Ajaya Kumar Reka

Rork Kuick

Himabindu Kurapati

Theodore J Standiford

Gilbert S Omenn

Venkateshwar G Keshamouni

Affiliations

Soon will be listed here.

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.

Citing Articles

Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.

Bhowmick R, Campit S, Katkam S, Keshamouni V, Chandrasekaran S Commun Biol. 2024; 7(1):1704.

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Systematic computational strategies for identifying protein targets and lead discovery.

Kataria A, Srivastava A, Singh D, Haque S, Han I, Yadav D RSC Med Chem. 2024; 15(7):2254-2269.

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Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells.

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Systemic sclerosis biomarkers detection in the secretome of TGFβ1-activated primary human lung fibroblasts.

Kendall R, Renaud L, Baatz J, Malaab M, Nguyen X, Feghali-Bostwick C J Proteomics. 2021; 242:104243.

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miR-944 Suppresses EGF-Induced EMT in Colorectal Cancer Cells by Directly Targeting GATA6.

Tang J, Gao W, Liu G, Sheng W, Zhou J, Dong Q Onco Targets Ther. 2021; 14:2311-2325.

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