@phdthesis{oai:nagasaki-u.repo.nii.ac.jp:00004747,
 author = {谷口, 広明},
 month = {Mar},
 note = {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., 長崎大学学位論文 学位記番号:博(医歯薬)甲第761号 学位授与年月日:平成27年3月18日, Author: Hiroaki Taniguchi, Hiroo Hasegawa, Daisuke Sasaki, Koji Ando, Yasushi Sawayama, Daisuke Imanishi, Jun Taguchi, Yoshitaka Imaizumi, Tomoko Hata, Kunihiro Tsukasaki, Naoki Uno, Yoshitomo Morinaga, Katsunori Yanagihara, Yasushi Miyazaki, Citation: Cancer Science, 105(12), pp.1601-1608; 2014, Nagasaki University (長崎大学), 博士(医学) (2015-03-18)},
 school = {Nagasaki University (長崎大学)},
 title = {Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia?lymphoma cells},
 year = {2015}
}