Identifying Inhibitors of Epithelial-Mesenchymal Transition by Connectivity Map–Based Systems Approach Ajaya Kumar Reka, PhD, Rork Kuick, MS, Himabindu.

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Identifying Inhibitors of Epithelial-Mesenchymal Transition by Connectivity Map–Based Systems Approach Ajaya Kumar Reka, PhD, Rork Kuick, MS, Himabindu Kurapati, MSc, Theodore J. Standiford, MD, Gilbert S. Omenn, MD, PhD, Venkateshwar G. Keshamouni, PhD Journal of Thoracic Oncology Volume 6, Issue 11, Pages 1784-1792 (November 2011) DOI: 10.1097/JTO.0b013e31822adfb0 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1. Effect of rapamycin, 17-AAG and LY 294002 on Epithelial and mesenchymal markers during transforming growth factor-β (TGF-β) induced epithelial-mesenchymal transition (EMT). A549 or H358 cells were serum starved for 24 hours, pretreated with inhibitors and stimulated with or without TGF-β (5 ng/ml). After 72 hours, (A) E-cadherin and stress fibers (F-actin by Phalloidin staining) were assessed in A549 cells by immunofluorescence (scale bar 100 μm), (B) epithelial (E-cadherin) and mesenchymal (N-cadherin, vimentin) markers were assessed in A549 cells, (C) epithelial (E-cadherin) and mesenchymal (vimentin) markers in H358 cells were assessed by western immunoblotting. Quantitation of western immunoblotting data from three independent experiments was done by ImageJ software and presented in Supplementary Figure S1. Journal of Thoracic Oncology 2011 6, 1784-1792DOI: (10.1097/JTO.0b013e31822adfb0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2. Effect of rapamycin, 17-AAG and LY 294002 on migration and invasion during transforming growth factor-β (TGF-β) induced epithelial-mesenchymal transition (EMT): A549 or H358 cells were serum starved for 24 hours, stimulated with TGF-β (5 ng/ml) in the presence or absence of inhibitors at indicated concentrations. After 72 hours, cells were trypsinized and plated in uncoated or matrigel-coated transwell chambers to assess cellular migration and invasion, respectively. Error bars represent the standard deviation (SD) from three independent replicates. *Statistically significant (p < 0.05) difference when compared with TGF-β treated cells. Journal of Thoracic Oncology 2011 6, 1784-1792DOI: (10.1097/JTO.0b013e31822adfb0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3. Effect of rapamycin, 17-AAG and LY 294002 on transforming growth factor-β (TGF-β) induced Smad phosphorylation: A549 cells were serum starved for 24 hours, stimulated with TGF-β (5 ng/ml) in the presence or absence of inhibitors for 1 (A) or 4 (B) hours. Cell lysates were assessed for phospho-Smad 2 and 3 and total Smad 2 and 3 protein levels by western immunoblotting. Journal of Thoracic Oncology 2011 6, 1784-1792DOI: (10.1097/JTO.0b013e31822adfb0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4. Effect of rapamycin, 17-AAG and LY 294002 on transforming growth factor-β (TGF-β)-induced Smad functional activity: A549-SBE-Luc cells were serum starved for 24 hours, stimulated with TGF-β (5 ng/ml) in the presence or absence of inhibitors at indicated concentrations. After 4 hours, luciferase expression was measured and normalized to the protein concentrations. Error bars represent the standard deviation (SD) from three independent replicates. *Statistically significant (p < 0.05) difference when compared with TGF-β treated cells. Journal of Thoracic Oncology 2011 6, 1784-1792DOI: (10.1097/JTO.0b013e31822adfb0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions