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

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...

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Published in:International journal of molecular sciences 2019-03, Vol.20 (6), p.1292
Main Authors: Yoo, Jeong-Ju, Yu, Su Jong, Na, Juri, Kim, Kyungmin, Cho, Young Youn, Lee, Yun Bin, Cho, Eun Ju, Lee, Jeong-Hoon, Kim, Yoon Jun, Youn, Hyewon, Yoon, Jung-Hwan
Format: Article
Language:English
Subjects:
Angiogenesis
Antiangiogenic agents
Antiangiogenics
Apoptosis
Cell culture
Glycolysis
Hepatocellular carcinoma
Hexokinase
Hypoxia
Inhibitor drugs
Lactic acid
Liver cancer
Medical prognosis
Oxidative phosphorylation
Phosphorylation
Survival
Targeted cancer therapy
Tumor cells
Tumors
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms20061292