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Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia–lymphoma cells

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Title: Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia–lymphoma cells
Authors: Taniguchi, Hiroaki / Hasegawa, Hiroo / Sasaki, Daisuke / Ando, Koji / Sawayama, Yasushi / Imanishi, Daisuke / Taguchi, Jun / Imaizumi, Yoshitaka / Hata, Tomoko / Tsukasaki, Kunihiro / Uno, Naoki / Morinaga, Yoshitomo / Yanagihara, Katsunori / Miyazaki, Yasushi
Issue Date: 1-Dec-2014
Publisher: 日本癌学会 / Japanese Cancer Association
Citation: Cancer Science, 105(12), pp.1601-1608; 2014
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. This report first describes the effectiveness of a novel HSP90 inhibitor NVP-AUY922 to adult T-cell leukemia-lymphoma (ATL) cells.
Keywords: Adult T-cell leukemia-lymphoma / HSP90 inhibitors / NF-κB / NVP-AUY922 / PIM kinases
URI: http://hdl.handle.net/10069/35006
ISSN: 13479032
DOI: 10.1111/cas.12540
Rights: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. / This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/35006

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