Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth

Alexandra Aronin, Shira Amsili, Tatyana B. Prigozhina, Kobi Tzdaka, Jacob Rachmilewitz, Noam Shani, Mark L. Tykocinski, Michal Dranitzki Elhalel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background:New strategies for the treatment of hepatocellular carcinoma (HCC) are needed, given that currently available chemotherapeutics are inefficient. Since tumor growth reflects the net balance between pro-proliferative and death signaling, agents shifting the equilibrium toward the latter are of considerable interest. The TWEAK:Fn14 signaling axis promotes tumor cell proliferation and tumor angiogenesis, while TRAIL:TRAIL-receptor (TRAIL-R) interactions selectively induce apoptosis in malignant cells. Fn14•TRAIL, a fusion protein bridging these two pathways, has the potential to inhibit tumor growth, by interfering with TWEAK:Fn14 signaling, while at the same time enforcing TRAIL:TRAIL-R-mediated apoptosis. Consequently, Fn14•TRAIL's capacity to inhibit HCC growth was tested.Results:Fn14•TRAIL induced robust apoptosis of multiple HCC cell lines, while sparing non-malignant hepatocyte cell lines. Differential susceptibility to this agent did not correlate with expression levels of TRAIL, TRAIL-R, TWEAK and Fn14 by these lines. Fn14•TRAIL was more potent than soluble TRAIL, soluble Fn14, or a combination of the two. The requirement of both of Fn14•TRAIL's molecular domains for function was established using blocking antibodies directed against each of them. Subcutaneous injection of Fn14•TRAIL abrogated HCC growth in a xenograft model, and was well tolerated by the mice.Conclusions:In this study, Fn14•TRAIL, a multifunctional fusion protein originally designed to treat autoimmunity, was shown to inhibit the growth of HCC, both in vitro and in vivo. The demonstration of this fusion protein's potent anti-tumor activity suggests that simultaneous targeting of two signaling axes by a single fusion can serve as a basis for highly effective anti-cancer therapies.

Original languageAmerican English
Article numbere77050
JournalPLoS ONE
Volume8
Issue number10
DOIs
StatePublished - 10 Oct 2013
Externally publishedYes

Bibliographical note

Funding Information:
MDE has a research grant and consulting fee from KAHR Medical LTD. SA is employed by KAHR Medical LTD, NS CEO of KAHR Medical LTD, and MLT is a share holder and inventor - KAHR Medical LTD. F n14-TRAIL is a fusion protein protected by patents issued and licensed to KAHR medical, MLT is an inventor. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

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