Table 3.
Summary of targeting metabolic processes for the treatment of HCC
| Target | Biological functions | Model | Main Findings | Drugs | Reference |
|---|---|---|---|---|---|
| Glycolysis and glycogen metabolism | |||||
| HK2 | Rate-limiting enzyme in the first glycolysis step; converting glucose into glucose-6-phosphate. | DEN-HCC model and subcutaneous xenograft models | Hepatic HK2 deletion inhibited tumor incidence in a mouse model of hepatocarcinogenesis. HK2 silencing synergizes with sorafenib to inhibit tumor growth. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained. HK2 silencing in combination with metformin suppressed mTORC1 in an AMPK-independent and REDD1-dependent manner. | Metformin | [64, 117] |
| PKM2 | PKM2 is involved in the conversion of phosphoenolpyruvate to pyruvate. | Subcutaneous and orthotopic xenograft models | PKM2 is upregulated in HCC; knockdown of PKM2 hampered HCC growth in both subcutaneous injection and orthotopic liver implantation models and reduced lung metastasis in vivo. | N/A | [118] |
| Lipid metabolism | |||||
| FXR | Hepatic FXR is the primary regulator of bile acid biosynthesis with essential roles in fatty-acid homeostasis. | Genetic engineered mouse model | Kainuma et al. found that FXR activation enhanced TGFβ-induced epithelial-mesenchymal transition in HCC cells. However, Yang et al. reported spontaneous development of liver tumors in the absence of the FXR. | OCA | [119, 120] |
| FASN | FASN is the master regulator of de novo lipogenesis. | Hydrodynamic transfection induced HCC | Genetic deletion of Fasn inhibited tumor development in AKT, AKT/MET, Pten loss, and c-Myc mice. Blocking cholesterol biosynthesis in combination with liver-specific Fasn knockout prevents tumor formation in mice. | C75; TVB2640 | [67, 68] |
| TCA cycle | |||||
| PDK4 | PDK4 is a key enzyme regulating the central pathway of cell metabolism by inhibiting pyruvate dehydrogenase. | Subcutaneous xenograft model | Knockdown of PDK4 increased expression of key lipogenic enzymes, FASN and stearoyl-CoA desaturase, and silencing PDK4 facilitated proliferation and migration of HCC cells | [121] | |
| SDHB | Succinate dehydrogenase converts succinate into fumarate in the TCA cycle. | Subcutaneous xenograft model | Subcutaneous implantation and tail vein injection with SDHB knockdown cells resulted in a larger tumor volume and accelerated cancer metastasis, respectively. Silencing of SDHB altered energy metabolism switched from aerobic respiration to glycolysis, resulted in the Warburg effect, and enhanced cell proliferation and motility. | [122] | |
| Oxidative phosphorylation | |||||
| NANOG | NANOG is a transcription factor and can act as a bona fide oncogene to induce carcinogenesis. | Alcohol- or obesity-HCV-induced tumor models | NANOG is induced by Toll-like receptor 4 signaling via phosphorylation of E2F1, and downregulation of Nanog slowed down HCC progression. | [123] | |
| SALL4 | SALL4 is a transcription factor and can act as a bona fide oncogene to induce carcinogenesis. | PDX HCC model | Mitochondrial oxidative phosphorylation inhibitors were shown to be particularly effective in suppressing SALL4-expressing HCC tumorigenesis in culture and in vivo. SALL4 binds approximately 50% of mitochondrial genes, including many oxidative phosphorylation genes, to activate their transcription. Oligomycin also reduced the growth of xenograft tumors grown from SALL4hi SNU-398 or HCC26.1 cells to a greater extent than sorafenib. | Oligomycin | [124] |
| Pentose-phosphate pathway | |||||
| NRF2 /KEAP1 | NRF2 is a transcriptional factor, and KEPA1 is a major negative regulator of NRF2. Activation of NRF2 increases glucose uptake and directs it to the pentose phosphate pathway. | DEN-HCC | HBV upregulates G6PD expression by HBx-mediated activation of Nrf2. In HBV-infected hepatocytes, HBx, on the one hand, results in the accumulation of p62 through inhibition of autophagic flux, and on the other hand, interacts with Keap1 through p62, enabling the formation of HBx–p62–Keap1 aggregates in the cytoplasm. These aggregates hijack Keap1 from Nrf2 leading to Nrf2 activation and G6PD expression. Nrf2 mutagenic activation drives hepatocarcinogenesis. | [71, 125, 126] | |
| Amino acid metabolism | |||||
| OGDHL | OGDHL is one of the rate-limiting components of OGDH complex, in the regulation of lipid metabolism. | Subcutaneous xenograft | The silencing of OGDHL induces lipogenesis and influences the chemosensitization effect of sorafenib in liver cancer cells by reprogramming glutamine metabolism. The reduction of reductive glutamine metabolism through OGDHL overexpression or glutaminase inhibitors sensitized tumor cells to sorafenib, a molecular-targeted therapy for HCC. | [127] | |
| p300/CBP | p300/CBP transcriptional coactivator proteins are central regulators of epigenetics. | PDX HCC model | p300/CBP epigenetically regulated the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC. These data highlight the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. p300/CBP regulates the expression of the enzyme genes related to amino acid metabolism and nucleotide synthesis. | B029-2 | [72] |
| Purine metabolism | |||||
| IMPDH | IMPDH is a purine biosynthetic rate-limiting enzyme. | PDX HCC model | Targeted ablation of purine biosynthesis by knockdown of the IMPDH or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. | MMF | [128] |
Abbreviations: HK2, Hexokinase 2; PKM2, Pyruvate kinase M2; OCA, obeticholic acid; FXR, Farnesoid X receptor; FASN, Fatty acid synthase; PDK4, Pyruvate dehydrogenase kinase 4; SDHB, Succinate dehydrogenase B; NRF2, Nuclear factor erythroid 2-related factor 2; KEAP1, Kelch-like ECH-associated protein 1; OGDHL, oxoglutarate dehydrogenase-like; CBP, CREB Binding Protein; IMDPH, Inosine-5’-monophosphate dehydrogenase.