title: Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer.
abstract: Radiotherapy is used to treat many different human tumors. Paradoxically, radiation can activate TGF-β1 signaling and induce the epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor progression. This study investigated the inhibitory effects of halofuginone, a plant-derived alkaloid that has been shown to inhibit TGF-β1 signaling, on radiation-induced EMT and explored the underlying mechanisms using a Lewis lung carcinoma (LLC) xenograft model. The cells and animals were divided into five treatment groups: Normal Control (NC), Halofuginone alone (HF), Radiotherapy alone (RT), Radiotherapy combined with Halofuginone (RT+HF), and Radiotherapy combined with the TGF-β1 inhibitor SB431542 (RT+SB). Radiation induced EMT in lung cancer cells and xenografts, as evidenced by increased expression of the mesenchymal markers N-cadherin and Vimentin, and reduced expression of the epithelial markers E-cadherin and Cytokeratin. Further, radiotherapy treatment increased the migration and invasion of LLC cells. Halofuginone reversed the EMT induced by radiotherapy in vitro and in vivo, and inhibited the migration and invasion of LLC cells. In addition, TGF-β1/Smad signaling was activated by radiotherapy and the mRNA expression of Twist and Snail was elevated; this effect was reversed by halofuginone or the TGF-β1 inhibitor SB431542. Our results demonstrate that halofuginone inhibits radiation-induced EMT, and suggest that suppression of TGF-β1 signaling may be responsible for this effect.
authors.affiliation: Department of Radiation Oncology, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pain Management, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Weishuai
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Peking University International Hospital, Beijing 102206, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Hailing
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Radiation Oncology, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Ningbo
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Radiation Oncology, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Youyou
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pain Management, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Ji
authors.affiliation: Department of Radiation Oncology, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Lujun
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D002465:Cell Movement / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000528:radiation effects; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D010880:Piperidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D051785:Smad Proteins / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004149:Dioxoles; D010880:Piperidines; D052999:Quinazolinones; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C010176:halofuginone
keywords: epithelial-mesenchymal transition (EMT); halofuginone; lung cancer; radiotherapy; transforming growth factor-β (TGF-β1)