title: A mitochondrial thioredoxin-sensitive mechanism regulates TGF-β-mediated gene expression associated with epithelial-mesenchymal transition.
abstract: Transforming growth factor (TGF)-β is a pro-oncogenic cytokine that induces the epithelial-mesenchymal transition (EMT), a crucial event in tumor progression. During TGF-β-mediated EMT in NMuMG mouse mammary epithelial cells, we observed sustained increases in reactive oxygen species (ROS) levels in the cytoplasm and mitochondria with a concomitant decrease in mitochondrial membrane potential and intracellular glutathione levels. In pseudo ρ0 cells, whose respiratory chain function was impaired, the increase in intracellular ROS levels was abrogated, suggesting an important role of mitochondrial activity as a trigger for TGF-β-stimulated ROS generation. In line with this, TGF-β-mediated expression of the EMT marker fibronectin was inhibited not only by chemicals that interfere with ROS signaling but also by exogenously expressed mitochondrial thioredoxin (TXN2) independent of Smad signaling. Of note, TGF-β-mediated induction of HMGA2, a central mediator of EMT and metastatic progression, was similarly impaired by TXN2 expression, revealing a novel mechanism involving a thiol oxidation reaction in mitochondria, which regulates TGF-β-mediated gene expression associated with EMT.
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Ishikawa
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kaneko
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sugimoto
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishijima
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Wakamatsu
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yuasa
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Ruriko
authors.initials: R
authors.lastname: Sampei
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nose
authors.affiliation: Department of Molecular Biology, Division of Cancer Cell Biology, Showa University School of Pharmacy, Tokyo 142-8555, Japan. Electronic address: smotoko@pharm.showa-u.ac.jp.
authors.forename: Motoko
authors.initials: M
authors.lastname: Shibanuma
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D024003:HMGA Proteins / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013879:Thioredoxins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D024003:HMGA Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C467002:TXN2 protein, human; D016212:Transforming Growth Factor beta; D013879:Thioredoxins
keywords: Fibronectin; HMGA2; Mitochondria; ROS; TGF-β; TXN2