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Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth

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 ar...

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Autores principales: Aronin, Alexandra, Amsili, Shira, Prigozhina, Tatyana B., Tzdaka, Kobi, Rachmilewitz, Jacob, Shani, Noam, Tykocinski, Mark L., Dranitzki Elhalel, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794952/
https://www.ncbi.nlm.nih.gov/pubmed/24130833
http://dx.doi.org/10.1371/journal.pone.0077050
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author Aronin, Alexandra
Amsili, Shira
Prigozhina, Tatyana B.
Tzdaka, Kobi
Rachmilewitz, Jacob
Shani, Noam
Tykocinski, Mark L.
Dranitzki Elhalel, Michal
author_facet Aronin, Alexandra
Amsili, Shira
Prigozhina, Tatyana B.
Tzdaka, Kobi
Rachmilewitz, Jacob
Shani, Noam
Tykocinski, Mark L.
Dranitzki Elhalel, Michal
author_sort Aronin, Alexandra
collection PubMed
description 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.
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spelling pubmed-37949522013-10-15 Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth Aronin, Alexandra Amsili, Shira Prigozhina, Tatyana B. Tzdaka, Kobi Rachmilewitz, Jacob Shani, Noam Tykocinski, Mark L. Dranitzki Elhalel, Michal PLoS One Research Article 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. Public Library of Science 2013-10-10 /pmc/articles/PMC3794952/ /pubmed/24130833 http://dx.doi.org/10.1371/journal.pone.0077050 Text en © 2013 Aronin et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Aronin, Alexandra
Amsili, Shira
Prigozhina, Tatyana B.
Tzdaka, Kobi
Rachmilewitz, Jacob
Shani, Noam
Tykocinski, Mark L.
Dranitzki Elhalel, Michal
Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth
title Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth
title_full Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth
title_fullStr Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth
title_full_unstemmed Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth
title_short Fn14•Trail Effectively Inhibits Hepatocellular Carcinoma Growth
title_sort fn14•trail effectively inhibits hepatocellular carcinoma growth
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794952/
https://www.ncbi.nlm.nih.gov/pubmed/24130833
http://dx.doi.org/10.1371/journal.pone.0077050
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