Fn14·TRAIL fusion protein is oligomerized by TWEAK into a superefficient TRAIL analog

Tatyana B. Prigozhina, Fanny Szafer, Alexandra Aronin, Kobi Tzdaka, Shira Amsili, Efi Makdasi, Noam Shani, Michal Dranitzki Elhalel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageAmerican English
Pages (from-to)99-109
Number of pages11
JournalCancer Letters
StatePublished - 1 Aug 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier B.V.


  • Apoptosis
  • Fn14·TRAIL
  • Fusion protein
  • Oligomerization


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