title: Attenuation of reactive oxygen species by antioxidants suppresses hypoxia-induced epithelial-mesenchymal transition and metastasis of pancreatic cancer cells.
abstract: Hypoxia has been shown to promote metastasis of cancer cells through induction of epithelial-mesenchymal transition (EMT). It is also known to cause generation of reactive oxygen species (ROS). We investigated here the role of ROS in hypoxia-induced EMT and whether attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastasis of human pancreatic cancer cells in a xenograft nude mouse model. PANC-1 and MiaPaCa-2 cells exposed to hypoxia (1 % O(2)) showed increased ROS generation and characteristic changes of EMT such as morphological changes, enhanced invasiveness, and upregulation of EMT regulators, SLUG, SNAI1 and TWIST. The antioxidants N-acetylcysteine (NAC) and ebselen significantly suppressed EMT and the expression of EMT regulators during hypoxia. NAC abrogated activation of HIF-1α and NF-κB, both of which were found to play an active role in hypoxia-induced EMT. Administration of NAC to nude mice with orthotopic tumors suppressed the expression of EMT regulators in hypoxic areas and significantly inhibited hepatic metastasis. Together, the present findings demonstrate that attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastatic phenotype, suggesting that antioxidants may be of therapeutic value in treating pancreatic cancers.
authors: Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane, Japan.
authors: Yoshihide
authors: Y
authors: Shimojo
authors: Miho
authors: M
authors: Akimoto
authors: Tsunehiro
authors: T
authors: Hisanaga
authors: Tsuneo
authors: T
authors: Tanaka
authors: Yoshitsugu
authors: Y
authors: Tajima
authors: Yoshio
authors: Y
authors: Honma
authors: Keizo
authors: K
authors: Takenaga
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000111:Acetylcysteine