Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinomaopen access
- 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
- Issue Date
- 21-Mar-2019
- Publisher
- Multidisciplinary Digital Publishing Institute (MDPI)
- Keywords
- hepatocellular carcinoma; sorafenib; hexokinase inhibitor; bromopyruvate
- Citation
- International Journal of Molecular Sciences, v.20, no.6
- Journal Title
- International Journal of Molecular Sciences
- Volume
- 20
- Number
- 6
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/4645
- DOI
- 10.3390/ijms20061292
- ISSN
- 1661-6596
1422-0067
- 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.
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