The Role of Lipid Metabolism in Gastric Cancer

Abstract

Gastric cancer has been one of the most common cancers worldwide with extensive metastasis and high mortality. Chemotherapy has been found as a main treatment for metastatic gastric cancer, whereas drug resistance limits the effectiveness of chemotherapy and leads to treatment failure. Chemotherapy resistance in gastric cancer has a complex and multifactorial mechanism, among which lipid metabolism plays a vital role. Increased synthesis of new lipids or uptake of exogenous lipids can facilitate the rapid growth of cancer cells and tumor formation. Lipids form the structural basis of biofilms while serving as signal molecules and energy sources. It is noteworthy that lipid metabolism is capable of inducing drug resistance in gastric cancer cells by reshaping the tumor micro-environment. In this study, new mechanisms of lipid metabolism in gastric cancer and the metabolic pathways correlated with chemotherapy resistance are reviewed. In particular, we discuss the effects of lipid metabolism on autophagy, biomarkers treatment and drug resistance in gastric cancer from the perspective of lipid metabolism. In brief, new insights can be gained into the development of promising therapies through an in-depth investigation of the mechanism of lipid metabolism reprogramming and resensitization to chemotherapy in gastric cancer cells, and scientific treatment can be provided by applying lipid-key enzyme inhibitors as cancer chemical sensitizers in clinical settings.

Keywords: biomarkers; chemoresistance; gastric cancer; lipid metabolism; treatment.

Figure 1

Overview of fatty acid metabolism reprogramming in gastric cancer cells. The process primarily includes de novo lipid synthesis, fatty acid oxidation, cholesterol synthesis, formation, as well as lipolysis of lipid droplets. Orange circles represent vital enzymes in lipid metabolism pathways. CPT1, carnitine palmitoyl transferase 1; FAs, fatty acids; FAO, fatty acid oxidation; TCA, Tricarboxylic Acid; LDs, lipid droplets; MUFA, Mono-unsaturated fatty acids; PUFA, polyunsaturated fatty acids; DGAT1/2, diacylglycerol O-acyltransferases 2; ATGL, Adipose triglyceride lipase; MGLL, monoglyceride lipase; ELOVL5, elongation of very long-chain fatty acid protein 5; FADS1, fatty acid desaturase 1; SOAT1, Sterol O-acyltransferase 1; LXRs, Liver X receptors; CD36, Cluster of differentiation 36; LDLR, low-density lipoprotein receptor; FABPs, fatty acid-binding proteins; ACSS2, acetyl-CoA synthetase 2;CPT1A, carnitine acyltransferase 1 A; CPT1C, carnitine acyltransferase 1 C; ATGL, adipose triglyceride lipase; HSL, hormone-sensitive lipase; MGLL, monoglyceride lipase.

Figure 2

Targeting signaling pathways in gastric cancer. Schematic representation of the Wnt, hedgehog, PI-3K, and Hippo pathways in GC. The purple circles represent lipid metabolism-related pathways in gastric cancer, and the blue circles represent signaling pathways in gastric cancer. YAT/PAZ, Yes-associated protein/transcriptional coactivator with PDZ-binding motif; LAT1/2 represents Large tumor suppressor 2; MST1/2, Macrophage stimulating 1/2; SREBPs, sterol regulatory element-binding protein; Pre-SREBPs, Pre-sterol regulatory element-binding protein; HMGCR, 3-hydroxy-3-methyl-glutaryl-CoA reductase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; ACLY, ATP-citrate lyase; ACC1, acetyl-CoA carboxylase; ELOVL6, fatty acid elongate 6; PA, phosphatidic acid; PI-3K/AKT/MTORC1, phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) signaling; DVL, Doppler Velocity Log; APC, Adenomatous polyposis coli; GGPP, geranylgeranyl pyrophosphate; CSCs, cancer stem cell; FZD7, Wnt receptor frizzled7.

Figure 3

Summary of small-molecule inhibitors of lipogenic enzymes in gastric cancer. In orange circles are the names of inhibitors for different vital enzymes for blocking the related pathways.

Figure 4

Lipid reprogramming in the tumor microenvironment affects the inter-cellular lipid metabolism and drug resistance of immune cells. Different immune cells in the TME of gastric cancer have different lipid metabolism changes, thus affecting their functions. The above metabolically reprogrammed immune cells exert different effects on GC. MSCs, Mesenchymal stem cell; CAFs, Cancer-associated fibroblasts; FFAs, free fatty acids; MACC1, Metastasis Associated in Colon Cancer 1; PITPNC1, Phosphatidylinositol transfer protein represents cytoplasmic 1; ACOT4, The acyl-CoA thioesterase 4; ALOX15, arachidonate lipoxygenase 15; Treg cells, regulatory T cells; TAMs, tumor-associated macrophages; DCs, dendritic cells; TAMs, tumor-associated macrophages; Trm cell, tissue-resident memory T cell.