title: Thioredoxin-binding protein-2 (TBP-2/VDUP1/TXNIP) regulates T-cell sensitivity to glucocorticoid during HTLV-I-induced transformation.
abstract: Although glucocorticoid (GC) is widely used for treating hematopoietic malignancies including adult T-cell leukemia (ATL), the mechanism by which leukemic cells become resistant to GC in the clinical course remains unclear. Using a series of T-cell lines infected with human T lymphotropic virus type-I (HTLV-I), the causative virus of ATL, we have dissected the transformation from interleukin (IL)-2-dependent to -independent growth stage. The transformation associates the loss of thioredoxin-binding protein-2 (TBP-2), a tumor suppressor and regulator of lipid metabolism. Here we show that TBP-2 is responsible for GC-induced apoptosis in ATL cells. In the IL-2-dependent stage, dexamethasone induced TBP-2 expression and apoptosis, both of which were blocked by GC receptor (GR) antagonist RU486. Knockdown of TBP-2 consistently reduced the amount of GC-induced apoptosis. In IL-2-independent stage, however, expression of GR and TBP-2 was suppressed and GC failed to induce apoptosis. Forced expression of GR led the cells to mild sensitivity to GC, which was also accomplished by treatment with suberoylanilide hydroxamic acid, a TBP-2 inducer. A transfection experiment showed that TBP-2 expression induced apoptosis in IL-2-independent ATL cells. Thus, TBP-2 is likely to be one of the key molecules for GC-induced apoptosis and a potential target for treating the advanced stage of ATL.
authors.affiliation: Laboratory of Infection and Prevention, Department of Biological Response, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: D A
authors.initials: DA
authors.lastname: Lopez-Ramos
authors.forename: E
authors.initials: E
authors.lastname: Yoshihara
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: H
authors.initials: H
authors.lastname: Masutani
authors.forename: K
authors.initials: K
authors.lastname: Sugie
authors.forename: M
authors.initials: M
authors.lastname: Maeda
authors.forename: J
authors.initials: J
authors.lastname: Yodoi
mesh_terms: D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D002460:Cell Line; D002472:Cell Transformation, Viral; D005938:Glucocorticoids / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D002352:Carrier Proteins; D005938:Glucocorticoids; D006877:Hydroxamic Acids; D011965:Receptors, Glucocorticoid; C486715:TXNIP protein, human; D000077337:Vorinostat