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

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

Abstract

This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhancesthe efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate theprognostic 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 andorthotopic tumor xenograftmodels in BALB/c nu/numice. The prognostic role of HK-II was evaluatedin data from HCC patients in The Cancer Genome Atlas (TCGA) database and validated in patientstreated with sorafenib. Quantitative real-time PCR, western blot analysis, and immunohistochemicalstaining revealed that HK-II expression is upregulated in the presence of sorafenib. Further analysis ofthe endoplasmic reticulum-stress network model in two different murine HCC models showed that theintroduction of additional stress by 3-BP treatment synergistically increased the in vivo/vitro efficacy ofsorafenib. We found that HCC patients with increased HK-II expression in the TCGA database showedpoor overall survival, and also confirmed similar results for TCGA database HCC patients who hadundergone sorafenib treatment. These results suggest that HK-II is a promising therapeutic target toenhance the efficacy of sorafenib and that HK-II expression might be a prognostic factor in HCC.

• DOI: https://doi.org/10.3390/ijms20061292
• ISBN or ISSN: 1422-0067

• 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
• This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.