Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma
AbstractThis 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. View Full-Text
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Yoo, J.-J.; Yu, S.J.; Na, J.; Kim, K.; Cho, Y.Y.; Lee, Y.B.; Cho, E.J.; Lee, J.-H.; Kim, Y.J.; Youn, H.; Yoon, J.-H. Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2019, 20, 1292.
Yoo J-J, Yu SJ, Na J, Kim K, Cho YY, Lee YB, Cho EJ, Lee J-H, Kim YJ, Youn H, Yoon J-H. Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2019; 20(6):1292.Chicago/Turabian Style
Yoo, Jeong-Ju; Yu, Su J.; Na, Juri; Kim, Kyungmin; Cho, Young Y.; Lee, Yun B.; Cho, Eun J.; Lee, Jeong-Hoon; Kim, Yoon J.; Youn, Hyewon; Yoon, Jung-Hwan. 2019. "Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma." Int. J. Mol. Sci. 20, no. 6: 1292.
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