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

Autor: Jeong-Ju Yoo, Jung Hwan Yoon, Young Youn Cho, Kyung Min Kim, Yun Bin Lee, Jeong Hoon Lee, Yoon Jun Kim, Juri Na, Su Jong Yu, Eun Ju Cho, Hyewon Youn
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
lcsh:Chemistry
0302 clinical medicine
Hexokinase
lcsh:QH301-705.5
Spectroscopy
Mice
Inbred BALB C
medicine.diagnostic_test
Liver Neoplasms
Drug Synergism
General Medicine
hepatocellular carcinoma
Sorafenib
Endoplasmic Reticulum Stress
Prognosis
Computer Science Applications
Up-Regulation
Gene Expression Regulation
Neoplastic
Treatment Outcome
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Immunohistochemistry
medicine.drug
Carcinoma
Hepatocellular
Cell Survival
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Western blot
Downregulation and upregulation
hexokinase inhibitor
In vivo
Cell Line
Tumor
medicine
Biomarkers
Tumor
Animals
Humans
Physical and Theoretical Chemistry
Pyruvates
Molecular Biology
neoplasms
Cell Proliferation
bromopyruvate
business.industry
Organic Chemistry
medicine.disease
Survival Analysis
Xenograft Model Antitumor Assays
In vitro
digestive system diseases
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Cell culture
Cancer research
business
Zdroj: International Journal of Molecular Sciences
Volume 20
Issue 6
International Journal of Molecular Sciences, Vol 20, Iss 6, p 1292 (2019)
ISSN: 1422-0067
Popis: 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.
Databáze: OpenAIRE
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