title: A modified version of galectin-9 suppresses cell growth and induces apoptosis of human T-cell leukemia virus type I-infected T-cell lines.
abstract: ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Galectins are a family of animal lectins that function both extracellularly (by interacting with cell surface and extracellular matrix glycoproteins and glycolipids) and intracellularly (by interacting with cytoplasmic and nuclear proteins) to modulate signaling pathways. We found that protease-resistant galectin-9 by modification of its linker peptide, hG9NC(null), prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells. The suppression of cell growth was inhibited by lactose, but not by sucrose, indicating that beta-galactoside binding is essential for hG9NC(null)-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of these genes are regulated by NF-kappaB, which plays a critical role in oncogenesis by HTLV-I. hG9NC(null) suppressed IkappaBalpha phosphorylation, resulting in suppression of NF-kappaB. Most importantly, treatment with hG9NC(null) (6.7 mg/kg injected intraperitoneally every day) reduced tumor formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into SCID mice. Our results suggest that hG9NC(null) could be a suitable agent for the management of ATL.
authors.affiliation: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Okudaira
authors.forename: Mitsuomi
authors.initials: M
authors.lastname: Hirashima
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Shoko
authors.initials: S
authors.lastname: Makishi
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomita
authors.forename: Takehiro
authors.initials: T
authors.lastname: Matsuda
authors.forename: Hirochika
authors.initials: H
authors.lastname: Kawakami
authors.forename: Naoya
authors.initials: N
authors.lastname: Taira
authors.forename: Kazuiku
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Masato
authors.initials: M
authors.lastname: Masuda
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takasu
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D005697:Galactosides / Q000378:metabolism; D037161:Galectins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D015490:HTLV-I Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000072597:Hepatitis A Virus Cellular Receptor 2; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011991:Receptors, Virus / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D005697:Galactosides; D037161:Galectins; D006131:Growth Inhibitors; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C091991:LGALS8 protein, human; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011991:Receptors, Virus; C007816:beta-galactoside; D001616:beta-Galactosidase; D020169:Caspases