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In the present study, we further analyzed the structure of BB\u2010PAC and elucidated the molecular mechanism underlying the inhibitory function of HTLV\u20101\u2010infected and ATL cells. After hot water extraction with fractionation with methanol\u2010acetone, BB\u2010PAC was found to be concentrated in fractions 4 to 7 (Fr7). The strongest inhibition of ATL cell growth was observed with Fr7, which contained the highest BB\u2010PAC polymerization degree of 14. The basic structure of BB\u2010PAC is mainly B\u2010type bonds, with A\u2010type bonds (7.1%) and cinchonain I units as the terminal unit (6.1%). The molecular mechanism of cytotoxicity observed around Fr7 against ATL cells was the degradation of JAK1 to 3 and the dephosphorylation of STAT3\/5, which occurs by proteasome\u2010dependent proteolysis, confirming that PAC directly binds to heat shock protein 90 (HSP90). JAK degradation was caused by proteasome\u2010dependent proteolysis, and we identified the direct binding of PAC to HSP90. In addition, the binding of cochaperone ATPase homolog 1 (AHA1) to HSP90, which is required for activation of the cofactor HSP90, was inhibited by BB\u2010PAC treatment. Therefore, BB\u2010PAC inhibited the formation of the HSP90\/AHA1 complex and promoted the degradation of JAK protein due to HSP90 dysfunction. These results suggest that the highly polymerized PAC component from blueberry leaves has great potential as a preventive and therapeutic agent against HTLV\u20101\u2010infected and ATL cells.<\/jats:p>","DOI":"10.1111\/cas.15277","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T18:09:58Z","timestamp":1643652598000},"page":"1406-1416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Inhibition of adult T\u2010cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis"],"prefix":"10.1111","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-5866","authenticated-orcid":false,"given":"Tomonaga","family":"Ichikawa","sequence":"first","affiliation":[{"name":"Division of Tumor and Cellular Biochemistry Department of Medical Sciences University of Miyazaki  Miyazaki 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Endocrinology Department of Internal Medicine Faculty of Medicine University of Miyazaki  Miyazaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-9950","authenticated-orcid":false,"given":"Kazuhiro","family":"Morishita","sequence":"additional","affiliation":[{"name":"Division of Tumor and Cellular Biochemistry Department of Medical Sciences University of Miyazaki  Miyazaki Japan"},{"name":"Project for Advanced Medical Research and Development Project Research Division Frontier Science Research Center University of Miyazaki  Miyazaki 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