Abstract
BackgroundSorafenib is the standard targeted drug used to treat hepatocellularcarcinoma (HCC), but the therapeutic response between individuals variesmarkedly. Recently, cytokine-based immunotherapy has been a topic of intensediscussion in the fight against cancer. The aim of this study was to explorewhether cytokine IL-2 could augment the anti-tumour effects of sorafenib onHCC.MethodsHepG2 and Huh7 cells were co-treated with sorafenib and IL-2 invitro, and cellular viability and death were analysed through the MTT assay,TUNEL staining, LDH release assay, and western blotting. Mitochondrial functionwas measured via ELISA, immunofluorescence, and western blotting. Pathwayblockers were used to establish the role of the JNK-TAZ pathways in regulatingcancer cell phenotypes.ResultsOur data demonstrated that sorafenib treatment increased the HCCapoptotic rate, repressed cell proliferation, and inhibited migratory responses,and these effects were enhanced by IL-2 supplementation. Mechanistically, thecombination of IL-2 and sorafenib interrupted mitochondrial energy metabolism bydownregulating mitochondrial respiratory proteins. In addition, IL-2 andsorafenib co-treatment promoted mitochondrial dysfunction, as evidenced by thedecreased mitochondrial potential, elevated mitochondrial ROS production,increased leakage of mitochondrial pro-apoptotic factors, and activation of themitochondrial death pathway. A molecular investigation revealed thatmitochondrial fission was required for the IL-2/sorafenib-mediated mitochondrialdysfunction. Mitochondrial fission was triggered by sorafenib and was largelyamplified by IL-2 supplementation. Finally, we found that IL-2/sorafenibregulated mitochondrial fission via the JNK-TAZ pathways; blockade of theJNK-TAZ pathways abrogated the inhibitory effects of L-2/sorafenib on cancersurvival, growth and mobility.ConclusionsAltogether, these data strongly suggest that additionalsupplementation with IL-2 enhances the anti-tumour activity of sorafenib bypromoting the JNK-TAZ-mitochondrial fission axis. This finding will pave the wayfor new treatment modalities to control HCC progression by optimizingsorafenib-based therapy.
Highlights
Sorafenib is the standard targeted drug used to treat hepatocellular carcinoma (HCC), but the therapeutic response between individuals varies markedly
As shown in Additional file 1: Figure S1, we found that neither IL-2 nor sorafenib treatment affected the viability of L02 cells, as assessed via MTT assay and LDH release assay
Caspase-3 activity increased in response to sorafenib treatment, and this effect was enhanced by IL-2 treatment (Fig. 1h, i)
Summary
Sorafenib is the standard targeted drug used to treat hepatocellular carcinoma (HCC), but the therapeutic response between individuals varies markedly. Targeted therapy has been tested in several clinical trials and has been proven to provide a survival advantage for patients with HCC. Sorafenib is the first approved targeted therapy drug and is the first-line FDA-approved tyrosine kinase inhibitor, improving the median overall survival time from 7.9 to 10.7 months in patients with HCC [4]. The clinical benefit of sorafenib treatment is limited to an overall increase in survival time of 3 months [8]. These data indicate the therapeutic potential of sorafenib against the progression of HCC but suggest that it is clinically necessary to optimize sorafenib-based treatment by combining it with other therapeutic strategies, such as immunotherapy
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