Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

Keywords: 1,3-BPG, 1,3-bisphosphoglycerate; 2-DG, 2-deoxy-d-glucose; 3-BrPA, 3-bromopyruvic acid; ACC, acetyl-CoA carboxylase; ACLY, adenosine triphosphate (ATP) citrate lyase; ACS, acyl-CoA synthease; AKT, protein kinase B; AML, acute myeloblastic leukemia; AMPK, adenosine mono-phosphate-activated protein kinase; ASS1, argininosuccinate synthase 1; ATGL, adipose triacylglycerol lipase; CANA, canagliflozin; CPT, carnitine palmitoyl-transferase; CYP4, cytochrome P450s (CYPs) 4 family; Cancer therapy; DNL, de novo lipogenesis; EMT, epithelial-to-mesenchymal transition; ER, endoplasmic reticulum; ERK, extracellular-signal regulated kinase; FABP1, fatty acid binding protein 1; FASN, fatty acid synthase; FBP1, fructose-1,6-bisphosphatase 1; FFA, free fatty acid; Fatty acid β-oxidation; G6PD, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLS1, renal-type glutaminase; GLS2, liver-type glutaminase; GLUT1, glucose transporter 1; GOT1, glutamate oxaloacetate transaminase 1; Glutamine metabolism; Glycolysis; HCC, hepatocellular carcinoma; HIF-1α, hypoxia-inducible factor-1 alpha; HK, hexokinase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; HSCs, hepatic stellate cells; Hepatocellular carcinoma; IDH2, isocitrate dehydrogenase 2; LCAD, long-chain acyl-CoA dehydrogenase; LDH, lactate dehydrogenase; LPL, lipid lipase; LXR, liver X receptor; MAFLD, metabolic associated fatty liver disease; MAGL, monoacyglycerol lipase; MCAD, medium-chain acyl-CoA dehydrogenase; MEs, malic enzymes; MMP9, matrix metallopeptidase 9; Metabolic dysregulation; NADPH, nicotinamide adenine nucleotide phosphate; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OTC, ornithine transcarbamylase; PCK1, phosphoenolpyruvate carboxykinase 1; PFK1, phosphofructokinase 1; PGAM1, phosphoglycerate mutase 1; PGK1, phosphoglycerate kinase 1; PI3K, phosphoinositide 3-kinase; PKM2, pyruvate kinase M2; PPARα, peroxisome proliferator-activated receptor alpha; PPP, pentose phosphate pathway; Pentose phosphate pathway; ROS, reactive oxygen species; SCD1, stearoyl-CoA-desaturase 1; SGLT2, sodium-glucose cotransporter 2; SLC1A5/ASCT2, solute carrier family 1 member 5/alanine serine cysteine preferring transporter 2; SLC7A5/LAT1, solute carrier family 7 member 5/L-type amino acid transporter 1; SREBP1, sterol regulatory element-binding protein 1; TAGs, triacylglycerols; TCA cycle, tricarboxylic acid cycle; TKIs, tyrosine kinase inhibitors; TKT, transketolase; Tricarboxylic acid cycle; VEGFR, vascular endothelial growth factor receptor; WD-fed MC4R-KO, Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO); WNT, wingless-type MMTV integration site family; mIDH, mutant IDH; mTOR, mammalian target of rapamycin.