Trichostatin A inhibits radiation-induced epithelial-to-mesenchymal transition in the alveolar epithelial cells
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Devipriya Nagarajan1,2, Lei Wang1, Weiling Zhao1,3 and Xiaochen Han3
1Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA
2School of Chemical & Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
3Tangshan People’s Hospital, Tangshan, Hebei, China
Weiling Zhao, email: email@example.com
Xiaochen Han, email: firstname.lastname@example.org
Keywords: TSA; EMT; TGF-beta; radiation; HDAC
Received: September 14, 2016 Accepted: August 29, 2017 Published: October 09, 2017
Radiation-induced pneumonitis and fibrosis are major complications following thoracic radiotherapy. Epithelial-to-mesenchymal transition (EMT) plays an important role in tissue injury leading to organ fibrosis, including lung. Our previous studies have reported that radiation can induce EMT in the type II alveolar epithelial cells in both in vitro and in vivo. HDAC inhibitors are a new family of anti-cancer agents currently being used in several clinical trials. In addition to their intrinsic anti-tumor properties, HDAC inhibition is also important in other human diseases, including fibrosis and radiation-induced damage. In this study, we evaluated the effect of Trichostatin A (TSA), a HDAC inhibitor, on radiation-induced EMT in type II alveolar epithelial cells (RLE-6TN). Pre-treatment of RLE-6TN cells with TSA inhibited radiation-induced EMT-like morphological alterations including elevated protein level of α-SMA and Snail, reduction of E-cadherin expression, enhanced phosphorylation of GSK3β and ERK1/2, increased generation of ROS. Radiation enhanced the protein level of TGF-β1, which was blocked by N-acetylcysteine, an antioxidant. Treating cells with SB-431542, TGF-β1 type I receptor inhibitor, diminished radiation-induced alterations in the protein levels of p-GSK-3β, Snail-1 and α-SMA, suggesting a regulatory role of TGF-β1 in EMT. Pre-incubation of cells with TSA showed significant decrease in the level of TGF-β1 compared to radiation control. Collectively, these results demonstrate that i] radiation-induced EMT in RLE-6TN cells is mediated by ROS/MEK/ERK and ROS/TGF-β1 signaling pathways and ii] the inhibitory role of TSA in radiation-induced EMT appears to be due, at least in part, to its action of blocking ROS and TGF-β1 signaling.
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