title: Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells.
abstract: Adult T-cell leukemia-lymphoma (ATL), an aggressive neoplasm etiologically associated with HTLV-1, is a chemoresistant malignancy. Heat shock protein 90 (HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. In this study, we examined NVP-AUY922 (AUY922), a second generation isoxazole-based non-geldanamycin HSP90 inhibitor, and confirmed its effects on survival of ATL-related cell lines. Analysis using FACS revealed that AUY922 induced cell-cycle arrest and apoptosis; it also inhibited the growth of primary ATL cells, but not of normal PBMCs. AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin. Interestingly, AUY922 induced downregulation of the proviral integration site for Moloney murine leukemia virus (PIM) in ATL cells. The PIM family (PIM-1, -2, -3) is made up of oncogenes that encode a serine/threonine protein kinase family. As PIM kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis, and tumorigenesis, their downregulation could play an important role in AUY922-induced death of ATL cells. In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines. Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target.
authors.affiliation: Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Hematology, Sasebo City General Hospital, Sasebo, Japan; Atomic Bomb Disease and Hibakusha Medicine Unit, Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sasaki
authors.forename: Koji
authors.initials: K
authors.lastname: Ando
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sawayama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Imanishi
authors.forename: Jun
authors.initials: J
authors.lastname: Taguchi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Imaizumi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hata
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsukasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Uno
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Morinaga
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000473:pathology*; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols
keywords: Adult T-cell leukemia-lymphoma; HSP90 inhibitors; NF-κB; NVP-AUY922; PIM kinases