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

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.

• Authors: Jeong-Ju Yoo, Su Jong Yu, Juri Na, Kyungmin Kim, Young Youn Cho, Yun Bin Lee, Eun Ju Cho, Jeong-Hoon Lee, Yoon Jun Kim, Hyewon Youn, Jung-Hwan Yoon
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 6 (Mar 14 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30875800 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Pyruvates
• bromopyruvate
• Sorafenib
• HK2 protein, human
• Hexokinase

Topics

• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hexokinase (genetics, metabolism)
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism)
• Male
• Mice, Inbred BALB C
• Prognosis
• Pyruvates (administration & dosage, pharmacology)
• Sorafenib (administration & dosage, pharmacology)
• Survival Analysis
• Treatment Outcome
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays