{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:12:55Z","timestamp":1791238375560,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,5]],"date-time":"2014-11-05T00:00:00Z","timestamp":1415145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2014,12]]},"abstract":"Adult T\u2010cell leukemia\u2013lymphoma (ATL<\/jats:styled-content>), an aggressive neoplasm etiologically associated with HTLV<\/jats:styled-content>\u20101, is a chemoresistant malignancy. Heat shock protein 90 (HSP<\/jats:styled-content>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<\/jats:styled-content>\u2010AUY<\/jats:styled-content>922 (AUY<\/jats:styled-content>922), a second generation isoxazole\u2010based non\u2010geldanamycin HSP<\/jats:styled-content>90 inhibitor, and confirmed its effects on survival of ATL<\/jats:styled-content>\u2010related cell lines. Analysis using FACS<\/jats:styled-content> revealed that AUY<\/jats:styled-content>922 induced cell\u2010cycle arrest and apoptosis; it also inhibited the growth of primary ATL<\/jats:styled-content> cells, but not of normal PBMC<\/jats:styled-content>s. AUY<\/jats:styled-content>922 caused strong upregulation of HSP<\/jats:styled-content>70, a surrogate marker of HSP<\/jats:styled-content>90 inhibition, and a dose\u2010dependent decrease in HSP<\/jats:styled-content>90 client proteins associated with cell survival, proliferation, and cell cycle in the G1<\/jats:sub> phase, including phospho\u2010Akt, Akt, IKK<\/jats:styled-content>\u03b1, IKK<\/jats:styled-content>\u03b2, IKK<\/jats:styled-content>\u03b3, Cdk4, Cdk6, and survivin. Interestingly, AUY<\/jats:styled-content>922 induced downregulation of the proviral integration site for Moloney murine leukemia virus (PIM<\/jats:styled-content>) in ATL<\/jats:styled-content> cells. The PIM<\/jats:styled-content> family (PIM<\/jats:styled-content>\u20101, \u20102, \u20103) is made up of oncogenes that encode a serine\/threonine protein kinase family. As PIM<\/jats:styled-content> kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis, and tumorigenesis, their downregulation could play an important role in AUY<\/jats:styled-content>922\u2010induced death of ATL<\/jats:styled-content> cells. In fact, SGI<\/jats:styled-content>\u20101776, a pan\u2010PIM<\/jats:styled-content> kinase inhibitor, successfully inhibited the growth of primary ATL<\/jats:styled-content> cells as well as ATL<\/jats:styled-content>\u2010related cell lines. Our findings suggest that AUY<\/jats:styled-content>922 is an effective therapeutic agent for ATL<\/jats:styled-content>, and PIM<\/jats:styled-content> kinases may be a novel therapeutic target.<\/jats:p>","DOI":"10.1111\/cas.12540","type":"journal-article","created":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T07:55:38Z","timestamp":1411977338000},"page":"1601-1608","source":"Crossref","is-referenced-by-count":24,"title":["Heat shock protein 90 inhibitor NVP<\/scp>\u2010AUY<\/scp>922 exerts potent activity against adult T\u2010cell leukemia\u2013lymphoma cells"],"prefix":"10.1111","volume":"105","author":[{"given":"Hiroaki","family":"Taniguchi","sequence":"first","affiliation":[{"name":"Department of Hematology Atomic Bomb Disease Institute Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan"},{"name":"Department of Hematology Sasebo City General Hospital Sasebo Japan"},{"name":"Atomic Bomb Disease and Hibakusha Medicine Unit Department of Hematology 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