Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer
Abstract
:1. Introduction
2. Hypoxic Tumor Microenvironment in HCC
3. HIF-Induced Metabolic Reprogramming under Hypoxia and Drug Resistance in HCC
3.1. HIF-Mediated Induction of Glucose Metabolism under Hypoxia
3.1.1. HIF-Mediated Induction of Glucose Metabolism under Hypoxia and TKI Resistance
3.1.2. HIF-Mediated Induction of Glucose Metabolism under Hypoxia and ICI Resistance
3.2. HIF-Mediated Induction of Lactate Metabolism under Hypoxia
HIF-Mediated Induction of Lactate Metabolism and ICI Resistance
3.3. HIF-Mediated Suppression of Mitochondrial Metabolism under Hypoxia
HIF-Mediated Suppression of Mitochondrial Metabolism under Hypoxia and TKI Resistance
3.4. HIF-Mediated Induction of Serine Metabolism under Hypoxia
HIF-Mediated Induction of Serine Metabolism under Hypoxia and TKI Resistance
3.5. HIF-Mediated Induction of Adenosinergic Metabolism under Hypoxia
HIF-Mediated Induction of Adenosinergic Metabolism under Hypoxia and ICI Resistance
4. Targeting Hypoxic HCC to Overcome Drug Resistance
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Metabolic Pathways | Genes | HIF-Inducible | Expression in Human HCC |
---|---|---|---|
Glucose Metabolism (Activated) | GLUT1, GLUT3, HK2, ALDA and GAPDH | Yes [30] | Overexpressed [19,32,36,37,38,39,40] |
PFKL, ALDC, TPI, PGK1, ENO1 and PKM | Yes [30] | Undetermined | |
Lactate Metabolism (Activated) | LDHA and MCT4 | Yes [26,41,42] | Overexpressed [20,43] |
Mitochondrial Metabolism (Suppressed) | PDK1, NDUFA4L2, COX4-2, miR-210, HEY1 | Yes [44,45,46,47,48,49] | Overexpressed [46,50,51] |
MXI-1 | Yes [52] | Undetermined | |
Serine Synthesis Pathway and Folate Cycle (Activated) | PHGDH, PSPH, SHMT2, MTHFD2 and MTHFD1L | Yes [28] | Overexpressed [53,54,55,56] |
PSAT | Yes [28] | Undetermined | |
Adenosinergic Metabolism (Activated) | CD39/CD39L1 and CD73 | Yes [57] | Overexpressed [58,59] |
Inhibitors | Targets | Combination Treatment | Synergistic Effects on Hypoxic HCC |
---|---|---|---|
2-DG | Glycolysis | Sorafenib (TKI) | Reduced cell viability, induced oxidative stress and apoptosis [63,64] |
3-BP | HK2 (glycolysis) | Sorafenib (TKI) | Reduced cell viability in vitro and suppressed HCC progression in vivo [40] |
DCA | PDK1 (mitochondrial activity) | Sorafenib (TKI) | Promoted apoptosis and induced oxidative stress in vitro and suppress HCC progression in vivo [61] |
NCT-503 | PHGDH (SSP) | Sorafenib, Regorafenib and Lenvatinib (TKIs) | Promoted apoptosis and induced oxidative stress in vitro and suppressed HCC progression in vivo [65] |
POM-1 | CD39L1 (adenosinergic metabolism) | Anti-PD-1 and anti-CTLA-4 antibodies (ICIs) | Promoted lymphocyte infiltration and suppressed HCC progression in vivo [58] |
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Bao, M.H.-R.; Wong, C.C.-L. Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer. Cells 2021, 10, 1715. https://doi.org/10.3390/cells10071715
Bao MH-R, Wong CC-L. Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer. Cells. 2021; 10(7):1715. https://doi.org/10.3390/cells10071715
Chicago/Turabian StyleBao, Macus Hao-Ran, and Carmen Chak-Lui Wong. 2021. "Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer" Cells 10, no. 7: 1715. https://doi.org/10.3390/cells10071715
APA StyleBao, M. H. -R., & Wong, C. C. -L. (2021). Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer. Cells, 10(7), 1715. https://doi.org/10.3390/cells10071715