Journal
DIGESTIVE AND LIVER DISEASE
Volume 49, Issue 6, Pages 697-704Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.dld.2017.01.146
Keywords
beta-Catenin; FH535; Glycolysis; HCC cell metabolism; Hepatocellular carcinoma; Mitochondrial ETC complexes; Mitochondrial respiration; Sorafenib
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Funding
- Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center [P30CA177558]
- Office of the Vice President for Research
- Markey Cancer Center
- NCI Center Core Support Grant [P30 CA177558]
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Treatment of advanced hepatocellular carcinoma (HCC) remains a challenge due to the high tumor heterogeneity. In the present study, we aim to evaluate the impact of the beta-catenin inhibitor, FH535, alone or in combination with the Ras/Raf/MAPK inhibitor Sorafenib, on the bioenergetics profiles of the HCC cell lines Huh7 and PLC/PRF/5. Single low-dose treatments with FH535 or Sorafenib promoted different effects on mitochondrial respiration and glycolysis in a cell type specific manner. However, the combination of these drugs significantly reduced both mitochondrial respiration and glycolytic rates regardless of the HCC cells. The significant changes in mitochondrial respiration observed in cells treated with the Sorafenib-FH535 combination may correspond to differential targeting of ETC complexes and changes in substrate utilization mediated by each drug. Moreover, the bioenergetics changes and the loss of mitochondrial membrane potential that were evidenced by treatment of HCC cells with the combination of FH535 and Sorafenib, preceded the induction of cell apoptosis. Overall, our results demonstrated that Sorafenib-FH535 drug combination induce the disruption of the bioenergetics of HCC by the simultaneous targeting of mitochondrial respiration and glycolytic flux that leads the synergistic effect on inhibition of cell proliferation. These findings support the therapeutic potential of combinatory FH535-Sorafenib treatment of the HCC heterogeneity by the simultaneous targeting of different molecular pathways. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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