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Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma

1
Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Gyeonggi-do 14584, Korea
2
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 03080, Korea
3
Department of Nuclear Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 03080, Korea
4
Department of Internal Medicine, Chung-Ang University Hospital, Seoul 03080, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(6), 1292; https://doi.org/10.3390/ijms20061292
Received: 14 February 2019 / Revised: 8 March 2019 / Accepted: 11 March 2019 / Published: 14 March 2019
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Abstract

This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhances the efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate the prognostic implication of HK-II expression in patients with HCC. We used 3-bromopyruvate (3-BP), a HK-II inhibitor to target HK-II. The human HCC cell line was tested as both subcutaneous and orthotopic tumor xenograft models in BALB/c nu/nu mice. The prognostic role of HK-II was evaluated in data from HCC patients in The Cancer Genome Atlas (TCGA) database and validated in patients treated with sorafenib. Quantitative real-time PCR, western blot analysis, and immunohistochemical staining revealed that HK-II expression is upregulated in the presence of sorafenib. Further analysis of the endoplasmic reticulum-stress network model in two different murine HCC models showed that the introduction of additional stress by 3-BP treatment synergistically increased the in vivo/vitro efficacy of sorafenib. We found that HCC patients with increased HK-II expression in the TCGA database showed poor overall survival, and also confirmed similar results for TCGA database HCC patients who had undergone sorafenib treatment. These results suggest that HK-II is a promising therapeutic target to enhance the efficacy of sorafenib and that HK-II expression might be a prognostic factor in HCC. View Full-Text
Keywords: hepatocellular carcinoma; sorafenib; hexokinase inhibitor; bromopyruvate hepatocellular carcinoma; sorafenib; hexokinase inhibitor; bromopyruvate
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Yoo, J.-J.; Yu, S.J.; Na, J.; Kim, K.; Cho, Y.Y.; Lee, Y.B.; Cho, E.J.; Lee, J.-H.; Kim, Y.J.; Youn, H.; Yoon, J.-H. Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2019, 20, 1292.

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