Open AccessHeat shock protein 90 inhibitor NVP ‐ AUY 922 exerts potent activity against adult T‐cell leukemia–lymphoma cells
Author(s) -
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
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12540
Subject(s) - protein kinase b , cancer research , cell growth , cell cycle , biology , downregulation and upregulation , cyclin dependent kinase 6 , kinase , leukemia , carcinogenesis , microbiology and biotechnology , chemistry , apoptosis , cyclin dependent kinase , immunology , signal transduction , cancer , biochemistry , genetics , gene
Adult T‐cell leukemia–lymphoma ( ATL ), an aggressive neoplasm etiologically associated with HTLV ‐1, is a chemoresistant malignancy. Heat shock protein 90 ( HSP 90) 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 ‐ AUY 922 ( AUY 922), a second generation isoxazole‐based non‐geldanamycin HSP 90 inhibitor, and confirmed its effects on survival of ATL ‐related cell lines. Analysis using FACS revealed that AUY 922 induced cell‐cycle arrest and apoptosis; it also inhibited the growth of primary ATL cells, but not of normal PBMC s. AUY 922 caused strong upregulation of HSP 70, a surrogate marker of HSP 90 inhibition, and a dose‐dependent decrease in HSP 90 client proteins associated with cell survival, proliferation, and cell cycle in the G 1 phase, including phospho‐Akt, Akt, IKK α, IKK β, IKK γ, Cdk4, Cdk6, and survivin. Interestingly, AUY 922 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 AUY 922‐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 AUY 922 is an effective therapeutic agent for ATL , and PIM kinases may be a novel therapeutic target.