Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells.

摘要: // Feiyan Liu 1 , Xia Li Chunwan Lu 2,3 Aiping Bai 4 Jacek Bielawski Alicja Bielawska Brendan Marshall 5 Patricia V. Schoenlein Iryna O. Lebedyeva 6 and Kebin 2,3,7 College of Life Sciences, Zhejiang University, Hangzhou, China 2 Department Biochemistry Molecular Biology, Medical Georgia, Augusta, GA, USA 3 Charlie Norwood VA Center, University South Carolina, Charleston, SC, Cell Biology Anatomy, Chemistry Physics, Augusta 7 Georgia Cancer Correspondence to: Liu, email: Keywords : MDSCs, cathepsin, ceramide, autophagy flux, Lysosomal cell death, Immunology Microbiology Section, Immune response, Immunity Received October 10, 2016 Accepted November 07, Published 17, Abstract Myeloid-derived suppressor cells (MDSCs) are immune suppressive that hallmarks human cancer. MDSCs inhibit cytotoxic T lymphocytes (CTLs) NK functions to promote tumor escape progression, therefore considered key targets in cancer immunotherapy. Recent studies determined a role the apoptosis pathways tumor-induced MDSC homeostasis it is known ceramide plays regulation mammalian apoptosis. In this study, we aimed determine efficacy underlying molecular mechanism suppression MDSCs. Treatment tumor-bearing mice with LCL521, lysosomotropic inhibitor acid ceramidase, significantly decreased accumulation vivo . Using MDSC-like myeloid model, LCL521 lysosomes increases total cellular C16 level. Although have functional pathways, LCL521-induced death occurs an apoptosis- necroptosis-independent mechanism. treatment resulted increase number autophagic vesicles, heterolysosomes swollen ERs. Finally, concomitant inhibition cathepsin B D was required decrease death. Our observations indicate activate D, resulting interrupted ER stress culminates Therefore, ceramidase potentially effective adjunct therapeutic agent for enhance CTL-based