Fn14·TRAIL fusion protein is oligomerized by TWEAK into a superefficient TRAIL analog. (1st August 2017)

• Record Type: Journal Article
• Authors: Prigozhina, Tatyana B.; Szafer, Fanny; Aronin, Alexandra; Tzdaka, Kobi; Amsili, Shira; Makdasi, Efi; Shani, Noam; Dranitzki Elhalel, Michal
• Is Part Of: Cancer letters. Volume 400(2017)
• Page Start: 99
• Page End: 109
• Publication Date: 2017-08-01
• Subjects: Fn14·TRAIL -- Fusion protein -- TWEAK -- Apoptosis -- Oligomerization; TRAIL TNF-related apoptosis-inducing ligand -- TWEAK tumor necrosis factor-like weak inducer of apoptosis -- Fn14 fibroblast growth factor-inducible 14-kDa protein -- c-FLIP cellular Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein -- XIAP X chromosome-linked inhibitor of apoptosis -- PARP poly ADP ribose polymerase -- cIAP cellular inhibitor of apoptosis -- SMAC second mitochondria-derived activator of caspases -- RIP receptor-interacting protein -- PBL peripheral blood lymphocytes -- mAb monoclonal antibody -- IL interleukin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.04.026
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates specific anti-cancer activity, but insufficient efficacy in patients. A fusion protein Fn14·TRAIL, that combines soluble TRAIL molecule with a specific TWEAK receptor Fn14, is a better apoptosis-inducer for hepatocellular carcinomas than soluble TRAIL. However, Fn14·TRAIL does not effectively induce apoptosis in tumors of the lymphoid origin. As malignant cell apoptosis is strongly enhanced by secondary oligomerization of TRAIL, we tested the hypothesis that soluble Fn14·TRAIL can be oligomerized and become more active by adding TWEAK, a cytokine secreted in the tumor environment. We revealed that TWEAK and Fn14·TRAIL spontaneously formed a stable complex that induced apoptosis of malignant lymphoblasts earlier and more efficiently than TRAIL. The TWEAK-modified Fn14·TRAIL oligomer bound to target cells and delivered apoptotic signaling via TRAIL receptors. The oligomer induced faster and stronger cleavage of procaspase-8, -9, and -3; BID; poly-ADP ribose polymerase; and RIP compared to TRAIL. The oligomer also reduced expression of the anti-apoptotic proteins c-FLIP short and cIAP-1. Our data indicate that Fn14·TRAIL can be converted into a highly effective TRAIL oligomer upon binding to TWEAK. Highlights: A method improving apoptosis-inducing ability of TRAIL is proposed. The mechanism relies on fusion of Fn14 to TRAIL (forming Fn14·TRAIL fusion protein). TWEAK is the natural ligand of Fn14. TWEAK converts Fn14·TRAIL into an oligomer having super-efficient TRAIL activity.