title: Superoxide-Generating Nox5α Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and transforms T cells in vitro. To our knowledge, the functional role of reactive oxygen species (ROS)-generating NADPH oxidase 5 (Nox5) in HTLV-1 transformation remains undefined. Here, we found that Nox5α expression was upregulated in 88% of 17 ATL patient samples but not in normal peripheral blood T cells. Upregulation of the Nox5α variant was transcriptionally sustained by the constitutive Janus family tyrosine kinase (Jak)-STAT5 signaling pathway in interleukin-2 (IL-2)-independent HTLV-1-transformed cell lines, including MT1 and MT2, whereas it was transiently induced by the IL-2-triggered Jak-STAT5 axis in uninfected T cells. A Nox inhibitor, diphenylene iodonium, and antioxidants such as N-acetyl cysteine blocked proliferation of MT1 and MT2 cells. Ablation of Nox5α by small interfering RNAs abrogated ROS production, inhibited cellular activities, including proliferation, migration, and survival, and suppressed tumorigenicity in immunodeficient NOG mice. The findings suggest that Nox5α is a key molecule for redox-signal-mediated maintenance of the HTLV-1 transformation phenotype and could be a potential molecular target for therapeutic intervention in cancer development.
  
  
  OBJECTIVE
  HTLV-1 is the first human oncogenic retrovirus shown to be associated with ATL. Despite the extensive study over the years, the mechanism underlying HTLV-1-induced cell transformation is not fully understood. In this study, we addressed the expression and function of ROS-generating Nox family genes in HTLV-1-transformed cells. Our report provides the first evidence that the upregulated expression of Nox5α is associated with the pathological state of ATL peripheral blood mononuclear cells and that Nox5α is an integral component of the Jak-STAT5 signaling pathway in HTLV-1-transformed T cells. Nox5α-derived ROS are critically involved in the regulation of cellular activities, including proliferation, migration, survival, and tumorigenicity, in HTLV-1-transformed cells. These results indicate that Nox5α-derived ROS are functionally required for maintenance of the HTLV-1 transformation phenotype. The finding provides new insight into the redox-dependent mechanism of HTLV-1 transformation and raises an intriguing possibility that Nox5α serves as a potential molecular target to treat HTLV-1-related leukemia.
authors.affiliation: Department of Pediatrics, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Shigemura
authors.affiliation: Department of Pediatrics, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiohara
authors.affiliation: Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Furuta
authors.affiliation: Division of Tumor and Cellular Biochemistry, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kaneda
authors.affiliation: Division of Tumor and Cellular Biochemistry, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morishita
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Division of Virology, Niigata University Graduate School of Medicine and Dental Science, Niigata, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University, Munich, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Gorlach
authors.affiliation: Department of Pediatrics, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koike
authors.affiliation: Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan tohru_kamata@med.miyazaki-u.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kamata
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology* / Q000821:virology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D008565:Membrane Proteins; D009861:Onium Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; C007517:diphenyleneiodonium; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C431571:NOX5 protein, human; D053612:Janus Kinases; D000111:Acetylcysteine