Abstract LB-50: Ionizing radiation can enhance TGFss induced EMT: Investigation of signatures of cross-talk with the ATM pathway

Epithelial-mesenchymal transition (EMT), a process whereby epithelial cells undergo transition to a mesenchymal phenotype, has long been known to play a role in cellular differentiation during development and tumor invasion. EMT can be viewed as an extreme form of cell plasticity characterized by loss of epithelial markers, cytoskeletal reorganization, and transition to a spindle-shaped morphology concurrent with acquisition of mesenchymal markers. Whereas EMT can be induced by a wide array of stimuli and cytokines, TGFβ is considered to be a key player of the process. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGFβ activation in vivo, and also sensitizes human epithelial cells to undergo TGFβ-mediated EMT. In order to understand the likelihood of EMT following space radiation exposures to astronauts, we investigated possible interactions between the TGFβ and ATM pathway following radiation using hTERT immortalized human esophageal epithelial cells (EPC-hTERT), and mink lung epithelial cells (Mv1Lu). The identification of EMT can be shown in changes to morphology, related gene over expression or down regulation, which can be detected by RT-PCR, immunostaining and western blotting. Our study shows EMT can be induced by TGFβ alone, and a combination of heavy ion or proton radiation and TGFβ treatment in non-transformed Mv1Lu and EPC-hTERT cells can enhance the induction of EMT, with a dose as low as 0.1Gy. Pretreatment with TGFβRI inhibitor (SD208) can efficiently attenuate the Smad signaling pathway as detected by the phosphorylation of Smad2, as well as EMT. Serum deprival can also induce EMT-like phenotype in epithelial cells, which can be minimized by the TGFβRI inhibitor. In order to detail the role of the DNA damage response in EMT, we are studying inhibition of ATM or p53 in relation to TGFβ induced EMT. Results for cells irradiated in the presence of TGFβ, and the resulting function of ATM or p53 in the TGFβ mediated EMT process will be reported. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-50. doi:10.1158/1538-7445.AM2011-LB-50