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

作者：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

来源：CANCER SCIENCE, 2014, 105(12): 1601-1608.

DOI：10.1111/cas.12540

• Adult T-cell leukemia-lymphoma
• HSP90 inhibitors
• NF-B
• NVP-AUY922
• PIM kinases

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 G(1) phase, including phospho-Akt, Akt, IKK, IKK, IKK, 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.

• 出版日期2014-12