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- Title
Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma.
- Authors
Yoo, Jeong-Ju; Yu, Su Jong; Lee, Yun Bin; Cho, Eun Ju; Lee, Jeong-Hoon; Kim, Yoon Jun; Yoon, Jung-Hwan; Na, Juri; Kim, Kyungmin; Youn, Hyewon; Cho, Young Youn
- 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.
- Subjects
GLUCOKINASE; SORAFENIB; LIVER cancer; XENOGRAFTS; PATIENTS
- Publication
International Journal of Molecular Sciences, 2019, Vol 20, Issue 6, p1292
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms20061292