{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:31:59Z","timestamp":1776918719778,"version":"3.51.2"},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T00:00:00Z","timestamp":1580428800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Activation\u2010induced cell death (AICD) mediated by the Fas\/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK\/T\u2010cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL\u2010derived NK cell lines NK\u2010YS and Hank1, and primary lymphoma cells expressed procaspase\u20108\/FADD\u2010like interleukin\u20101\u03b2\u2010converting enzyme (FLICE) modulator and cellular FLICE\u2010inhibitory protein (c\u2010FLIP), along with Fas and FasL. Compared with Fas\u2010sensitive Jurkat cells, NK\u2010YS and Hank1 showed resistance to Fas\u2010mediated apoptosis in spite of the same expression levels of c\u2010FLIP and the death\u2010inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c\u2010FLIP (c\u2010FLIP<jats:sub>L<\/jats:sub>) was coimmunoprecipitated with Fas predominantly in both ENKL\u2010derived NK cell lines after Fas ligation. Indeed, c\u2010FLIP<jats:sub>L<\/jats:sub> was more sufficiently recruited to the DISC in both ENKL\u2010derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c\u2010FLIP<jats:sub>L<\/jats:sub> per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK\u2010YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c\u2010FLIP<jats:sub>L<\/jats:sub>, which prevents their Fas\u2010mediated apoptosis. Our results show that c\u2010FLIP<jats:sub>L<\/jats:sub> could be a promising therapeutic target against ENKL.<\/jats:p>","DOI":"10.1111\/cas.14296","type":"journal-article","created":{"date-parts":[[2020,1,7]],"date-time":"2020-01-07T07:35:44Z","timestamp":1578382544000},"page":"807-816","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Efficient recruitment of c\u2010FLIP<sub>L<\/sub> to the death\u2010inducing signaling complex leads to Fas resistance in natural killer\u2010cell lymphoma"],"prefix":"10.1111","volume":"111","author":[{"given":"Azuchi","family":"Masuda","sequence":"first","affiliation":[{"name":"Division of Hematology Department of Medicine Juntendo University School of Medicine Tokyo 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