Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives

Abstract

Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment.

Keywords: cancer; cholesterol; eicosanoid; fatty acid; glycerophospholipid; lipid droplet; metastasis; obesity; phenotypic switch; pseudo-EMT; sphingolipid.

Figure 1

Schematic overview of the lipid metabolic network that regulates melanoma progression. The figure highlights the lipid pathways that are mostly altered in melanoma cells: (1) the de novo synthesis, elongation and desaturation of fatty acids (FA), which produce the repertoire of FA with different saturation levels. (2) The import of FA from neighboring adipocytes that can fuel FA β-oxidation (FAO) in mitochondria (3) to produce energy. (4) The lipid droplets, composed of neutral lipids, i.e., triacylglycerol (TAG) and cholesteryl ester (CE), which are critical to melanoma cell aggressiveness. (5) The synthesis of glycerophospholipids (GPL), including phosphatidylcholine (PC), phosphatidylethanolamine (PE,) phosphatidylserine (PS) and phosphatidylinositol (PI), which are produced from glycerol-3-phosphate (G3P). (6) The synthesis of sphingolipids, which begins with the condensation of serine and FA-Coenzyme A conjugates. Sphingolipids and glyceroPL are precursors of lipid mediators involved in cell signaling pathways and are used to build cell membranes in order to sustain cancer cell proliferation. (7) The cholesterol biosynthesis, initiated by the conversion of acetyl-CoA to acetoacetyl-CoA, and (8) the cholesterol import from the bloodstream. Cholesterol and sphingolipids, i.e., sphingomyelin (SM) and gangliosides, are part of the lipid rafts, which act as signaling hubs in cancer cell proliferation, adhesion and migration. (9) The synthesis of prostaglandin E2 (PGE2) from arachidonic acid (AA), a long-chain polyunsaturated FA (PUFA) freed from phospholipids (PL). PGE2 and the sphingolipid metabolite S1P are secreted and act through cell surface receptors to suppress immune response and promote melanoma progression. Abbreviations: LPA, lysophosphatidic acid; MAG, monoacylglycerol; PA, phosphatidic acid; TCA, tricarboxylic acid.

Figure 2

Detailed view of the major alterations of lipid storage and metabolism pathways during melanoma development. Only lipid pathways with reported modifications in melanoma are represented. Enzymes, receptors and transporters are indicated in blue boxes. Modifications in melanoma are highlighted in red. Abbreviations: AA, arachidonic acid; ABC, ATP-binding cassette transporter; AC, acid ceramidase; ACAT, acyl-CoA: cholesterol acyltransferase; ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; ACS, acyl-CoA synthetase; ACSL3, acyl-CoA synthetase long chain 3; Akt, AKT serine/threonine kinase; A-SMase, acid sphingomyelinase; ATX, lysophospholipase D autotaxin; CE, cholesteryl ester; Cer, ceramide; CERS, ceramide synthase; CERT, ceramide transport protein; COX, cyclooxygenase; DAG, diacylglycerol; DDA, dendrogenin A; DEGS, dihydroceramide desaturase; d-GM3, de-N-acetyl GM3; ECHS1, enoyl-CoA hydratase short chain 1; EP, ethanolamine 1-phosphate; ER, endoplasmic reticulum; FA, fatty acid; FAO, fatty acid -oxidation; FASN, fatty acid synthase; FAT, fatty acid translocase; FABP, fatty acid binding protein; FATP, fatty acid transport protein; GALC, galactosylceramidase; GCase, glucosylceramidase; GCS, glucosylceramide synthase; GD3-S, GD3 synthase; GM2/GD2-S, GD2/GM2 synthase; GlcCer, glucosylceramide; GM3-S, GM3 synthase; GSL, glycosphingolipid; G3P, glycerol-3-phosphate; HADHA, hydroxyacyl-CoA dehydrogenase subunit alpha; HADHB, hydroxyacyl-CoA dehydrogenase subunit beta; hexa, hexadecenal; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HMGCR, HMG-CoA reductase; HMGCS, HMG-CoA synthase; KDSR, 3-ketosphinganine reductase; LacCer, lactosylceramide; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPA, lysophosphatidic acid; lysoPC, lysophosphatidylcholine; lysoPL, lysophospholipid; LXR, liver X receptors; MAG, monoacylglycerol; MAGL, monoacylglycerol lipase; NCDase, neutral ceramidase; NSMase, neutral sphingomyelinase; PA, phosphatidic acid; PC, phosphatidylcholine; PGE2, prostaglandin E2; PGES, prostaglandin E synthase; PGH2, prostaglandin H2; PI, phosphatidylinositol; PI3K, phosphatidylinositol-3-kinase; PIP3, phosphatidylinositol-3,4,5-triphosphate; PL, phospholipid; PLA2, phospholipase A2; PUFA, polyunsaturated fatty acid; S, sphingosine; SCD, stearoyl-CoA desaturase; sFA, saturated fatty acid; SM, sphingomyelin; SMS, sphingomyelin synthase; SphK, sphingosine kinase; SPL, sphingosine 1-phosphate lyase; SPNS2, sphingolipid transporter 2; SPT, serine palmitoyltransferase; SR-BI, scavenger receptor class B type I; SREBP2, sterol regulatory element binding protein 2; S1P, sphingosine 1-phosphate; TAG, triacylglycerol; TCA, tricarboxylic acid.