Abstract 1050: Alvespimycin (17-DMAG) blocks TGFβ-induced EMT and migration in A549 lung cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. 1050
• Main Authors: Gordian, Edna, Welsh, Eric, Muñoz-Antonia, Teresita
• Format: Journal Article
• Language: English
• Published: 01-10-2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-1050

Background: Transforming Growth Factor β (TGFβ) can induce Epithelial-to-Messenchymal Transition (EMT) in Non-Small Cell Lung Cancer (NSCLC) leading to increased potential to migrate and metastasize. A unique Tumor Promoting signature (TGFβ-TP97) with genes highly associated with TGFβ-induced EMT was derived from human lung cancer cell line microarray experiments. The TGFβ-TP97 EMT signature was then searched against the Connectivity Map (CMAP) dataset for drugs that induce gene expression changes opposite to those of the TGFβ-TP97 signature, and identified 17-DMAG as a compound that could potentially inhibit EMT in NSCLC cells. 17-DMAG is an Hsp90 inhibitor recently described to have a stronger antiproliferative effect in NSCLC harboring EGFR mutations over EGFR wild type lung cancers cells. Furthermore, 17-DMAG has been recently shown to prevent TGFβ induced fibrosis. Methods: A549 and A549T (A549 cells grown in the presence of TGFβ for over two weeks, that have acquired a mesenchymal/fibroblast-like phenotype) were treated with increasing concentrations of 17-DMAG, both in the absence and presence of 5ng/mL TGFβ, and proliferation was measured through GLO assay after 72 hours. The effects of 17-DMAG on TGFβ signaling was tested by Western Blotting for phosphorylated Smads and markers of TGFβ-induced EMT. 17-DMAG effects on morphology and migration were also determined through wound healing and invasion assays. Results: 1) A549T cells grown in TGFβ are more sensitive to the effects of 17-DMAG than cells grown without TGFβ; 2) Pre-treatment of A549 cells with 17-DMAG blocks the induction of EMT markers such as Snail and the downregulation of Ecadherin; 3) 17-DMAG blocks TGFβ-induced phosphorylation of SMAD2, SMAD3; and 4) 17-DMAG inhibits migration and decreases motility of A549 cells in the presence of TGFβ. Conclusion: These results show that 17-DMAG is a potent inhibitor of the effects of TGFβ-induced EMT in A549 cells. It interferes with the regulated process of TGFβ signaling by its ability to block Smad activation and induction of EMT proteins. These findings suggest that 17-DMAG can potentially be used in the treatment of NSCLC cells to prevent disease dissemination and invasion.
Citation Format: Edna Gordian, Eric Welsh, Teresita Muñoz-Antonia. Alvespimycin (17-DMAG) blocks TGFβ-induced EMT and migration in A549 lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1050. doi:10.1158/1538-7445.AM2014-1050