Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Abstract

Hypoxia, low oxygen (O₂) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

Keywords: ICIs; TKIs; drug resistance; hypoxia; liver cancer; metabolic reprogramming; metabolism.

Figure 1

Hypoxic tumor microenvironment (TME) in hepatocellular carcinoma (HCC). A gradually decreasing gradient of partial pressure of O₂ (pO₂) in HCC from the blood vessel. Tumor regions that are close to the blood vessel are more oxygenated whereas regions away from the blood vessel are hypoxic. HCC treatments including arterial embolization transcatheter (TAE), arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) inadvertently induced hypoxia in HCC.

Figure 2

Hypoxia-inducible factors (HIFs) divert metabolites from tricarboxylic acid cycle (TCA) cycle to glycolysis under hypoxia. (a) Under normoxia, glucose is converted to pyruvate during glycolysis. Pyruvate is then converted to acetyl coenzyme A (acetyl-CoA), which fuels the TCA cycle for maximum adenosine triphosphate (ATP) production with ample oxygen (O₂) supply. (b) Under hypoxia, metabolism is switched from oxidative to glycolytic metabolism by HIF-dependent upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and (lactate dehydrogenase A) LDHA. Lactate export is promoted to prevent excessive intracellular lactate accumulation, which may lead to cytoplasmic acidification. Serine synthesis pathway (SSP) and its downstream folate cycle are activated. Folate cycle produces a major antioxidant, nicotinamide adenine dinucleotide phosphate (NADPH), to counteract oxidative stress under hypoxia. Mitochondrial activity and biogenesis are suppressed to reduce mitochondrial reactive oxygen species (ROS) production. Genes or pathways highlighted in red: upregulated by HIFs. Genes or pathways highlighted in blue: downregulated by HIFs.

Figure 3

Electron transport chain (ETC). ETC is located at mitochondrial inner membrane (MIM). Electron donors produced from glycolysis and TCA cycle, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), and succinate (glucose intermediate) donate electrons to the ETC. Electrons pass through ETC complex I to IV and finally to O₂, the final electron accepter. Electron flow drives H⁺ export to the intermembrane space, creating a transmembrane electrical potential to drive ATP synthesis. Premature electron leakage leads to ROS accumulation, especially at complex I and complex III.

Figure 4

HIF-induced metabolic reprogramming under hypoxia creates an immunosuppressive TME. HIF-mediated induction of lactate metabolism and adenosinergic metabolism leads to the accumulation of oncometabolites, including lactate, adenosine monophosphate (AMP) and adenosine at TME that inhibits anti-tumoral immune cells and promotes expansion of protumoral immune cells, resulting in an immunosuppressive TME that aids immune evasion of tumor cells.