Abstract
Abstract HMLEs (HMLE-SNAIL and Kras-HMLE-SNAIL pairs) serve as excellent model system to interrogate the effect of SNAIL targeted agents that reverse epithelial-to-mesenchymal transition (EMT). We developed a SNAIL-p53 interaction inhibitor (GN-25) that was shown to suppress SNAIL function. In this report, using pathway network analysis, we show that GN-25 induces the reversal of EMT to mesenchymal-to-epithelial transition (MET) in well recognized HMLE-SNAIL and Kras-HMLE-SNAIL models. GN-25 induced MET was found to be concurrent with growth inhibition, suppression of spheroid forming capacity and induction of apoptosis. We performed systems and pathway network analysis on mRNA expression by microarrays from GN-25 treated Kras-HMLE-SNAIL cells that showed an orchestrated global re-organization of EMT network genes. The expression signatures were validated at the protein level using confocal microscopy, western blot analysis and time lapse videography, and we found down-regulation of mesenchymal markers such as TWIST1, TWIST2, ZEB-1 concurrently with up-regulation of epithelial marker E-Cadherin. Additionally, RNAi studies validated SNAIL dependent mechanism of action of the drug. Most importantly, GN-25 deregulated many major transcription factors (TFs) such as inhibition of oncogenic TFs Myc, TBX2, NR3C1 and enhancement in tumor suppressor TFs such as SMAD7, DD1T3, CEBPA, HOXA5, TFEB, IRF1, IRF7 and XBP1, resulting in MET as well as induction of cell death. Our systems and network investigations provide solid pre-clinical supportive evidence for clinical application of GN-25 for the reversal of EMT phenotype to MET in aggressive cancers. Citation Format: Asfar S. Azmi, Aliccia Bollig-Fisher, Bin Bao, Bum Joon-Park, SH Lee, Gyu-Yong Song, Ramzi M. Mohammad, Fazlul H. Sarkar. Network interrogations on SNAIL inhibitor GN-25 induced perturbations in HMLE-SNAIL cell line models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5234. doi:10.1158/1538-7445.AM2013-5234
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