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Cancer Cell International
Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary research

RETRACTED ARTICLE: IL-2 augments the sorafenib-induced apoptosis in liver cancer by promoting mitochondrial fission and activating the JNK/TAZ pathway

Authors: Xiaoyan Ding, Wei Sun, Jinglong Chen

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

Sorafenib is the standard targeted drug used to treat hepatocellular carcinoma (HCC), but the therapeutic response between individuals varies markedly. Recently, cytokine-based immunotherapy has been a topic of intense discussion in the fight against cancer. The aim of this study was to explore whether cytokine IL-2 could augment the anti-tumour effects of sorafenib on HCC.

Methods

HepG2 and Huh7 cells were co-treated with sorafenib and IL-2 in vitro, and cellular viability and death were analysed through the MTT assay, TUNEL staining, LDH release assay, and western blotting. Mitochondrial function was measured via ELISA, immunofluorescence, and western blotting. Pathway blockers were used to establish the role of the JNK-TAZ pathways in regulating cancer cell phenotypes.

Results

Our data demonstrated that sorafenib treatment increased the HCC apoptotic rate, repressed cell proliferation, and inhibited migratory responses, and these effects were enhanced by IL-2 supplementation. Mechanistically, the combination of IL-2 and sorafenib interrupted mitochondrial energy metabolism by downregulating mitochondrial respiratory proteins. In addition, IL-2 and sorafenib co-treatment promoted mitochondrial dysfunction, as evidenced by the decreased mitochondrial potential, elevated mitochondrial ROS production, increased leakage of mitochondrial pro-apoptotic factors, and activation of the mitochondrial death pathway. A molecular investigation revealed that mitochondrial fission was required for the IL-2/sorafenib-mediated mitochondrial dysfunction. Mitochondrial fission was triggered by sorafenib and was largely amplified by IL-2 supplementation. Finally, we found that IL-2/sorafenib regulated mitochondrial fission via the JNK-TAZ pathways; blockade of the JNK-TAZ pathways abrogated the inhibitory effects of L-2/sorafenib on cancer survival, growth and mobility.

Conclusions

Altogether, these data strongly suggest that additional supplementation with IL-2 enhances the anti-tumour activity of sorafenib by promoting the JNK-TAZ-mitochondrial fission axis. This finding will pave the way for new treatment modalities to control HCC progression by optimizing sorafenib-based therapy.
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Metadata
Title
RETRACTED ARTICLE: IL-2 augments the sorafenib-induced apoptosis in liver cancer by promoting mitochondrial fission and activating the JNK/TAZ pathway
Authors
Xiaoyan Ding
Wei Sun
Jinglong Chen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0671-3

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