Efficient recruitment of c-FLIPL to the death-inducing signaling complex leads to Fas resistance in natural killer-cell lymphoma.

Azuchi Masuda, Yasushi Isobe, Koichi Sugimoto, Mayumi Yoshimori, Ayako Arai, Norio Komatsu

Cancer science 2020 Mar

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Activation-induced 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-cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL-derived NK cell lines NK-YS and Hank1, and primary lymphoma cells expressed procaspase-8/FADD-like interleukin-1β-converting enzyme (FLICE) modulator and cellular FLICE-inhibitory protein (c-FLIP), along with Fas and FasL. Compared with Fas-sensitive Jurkat cells, NK-YS and Hank1 showed resistance to Fas-mediated apoptosis in spite of the same expression levels of c-FLIP and the death-inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c-FLIP (c-FLIPL ) was coimmunoprecipitated with Fas predominantly in both ENKL-derived NK cell lines after Fas ligation. Indeed, c-FLIPL was more sufficiently recruited to the DISC in both ENKL-derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c-FLIPL per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK-YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c-FLIPL , which prevents their Fas-mediated apoptosis. Our results show that c-FLIPL could be a promising therapeutic target against ENKL. © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Citation

Azuchi Masuda, Yasushi Isobe, Koichi Sugimoto, Mayumi Yoshimori, Ayako Arai, Norio Komatsu. Efficient recruitment of c-FLIPL to the death-inducing signaling complex leads to Fas resistance in natural killer-cell lymphoma. Cancer science. 2020 Mar;111(3):807-816