Lipid metabolism in cancer progression and therapeutic strategies

Abstract

Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune-associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

Keywords: cancer; lipid metabolism; mechanism; microenvironment; therapeutic strategy.

FIGURE 1

Lipid metabolism in cancer. Glutamine and glucose‐derived acetyl‐CoA are used in the de novo synthesis of cholesterol and fatty acids. In addition, exogeneous uptake also contributes to the fatty acid pool in cancer cells. Fatty acids can undergo β‐oxidation to generate ATP and acetyl‐CoA. FA‐derived acyl‐CoA and glucose‐derived glyverol 3‐phosphate serve the main material source for de novo synthesis of phospholipids Abbreviations: ACC, acetyl‐CoA carboxylase; ACLY, ATP‐citrate lyase; ACS, acyl‐CoA synthetase; CACT, carnitine acyl‐transferase; CD36, fatty acid translocase/scavenging receptor; FABPs, fatty acid‐binding proteins; FASN, fatty acid synthase; FPP, farnesylpyrophosphate; HMGCR, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase; HSL, hormone‐sensitive lipase; LDLR, low‐density lipoprotein receptor; MUFA, monounsaturated fatty acid; SCD, stearoyl‐CoA desaturase (D9); TAG, triacylglycerol.

FIGURE 2

Signaling pathways in lipid metabolic reprogramming. (A) The PI3K/Akt signaling pathway regulates lipid metabolism in cancer cells. PI3K/Akt can increase expression of FOXO1 leading to initiation of SREBP transcription. mTORC, a downstream target of PI3K/Akt signaling, can inhibit activation of LPIN, which will otherwise sequester SREBP and inhibit its translocation into nucleus. In addition, Akt can inhibit the activity of GSK3 to inhibit degradation of SREBP. (B) The Hippo signaling pathway regulates lipid metabolism in cancer cells. Noncannonical Hippo pathway regulates lipid metabolism through inhibiting the maturation of SREBP via preventing its translocation from ER to Golgi. LATS1/2 also promotes YAP/TAZ degradation, which will otherwise initiate the expression of FAO‐related genes to promote FA oxidation in cancer cells. In addition, YAP can also interact with SREBP in the nucleus to enhance its transcriptional activity and increasing expression of downstream targets such as HMGCR and fatty acids synthase. (C) p38 MAPK participates in the regulation of lipid metabolism via direct phosphorylation of PGC‐1α to facilitate recruitment of the coactivator to PPARγ target genes and driving chromatin remodeling, promoting PPARγ‐dependent gene transcription Abbreviations: ACLY, ATP‐citrate lyase; ACOX1, acyl‐CoA oxidase 1; CPT, carnitine palmitoyltransferase; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; EP300, E1A binding protein p300; FAS, fatty acid synthesis; FASN, fatty acid synthase; FOXO1, forkhead box O1; GSK3, glycogen synthase kinase 3; HMGCR, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase; HSL, hormone‐sensitive lipase; LATS1/2, large tumor suppressor kinase 1/2; LDLR, low‐density lipoprotein receptor; M‐ SREBP, mature SREBP; MST1/2, macrophage stimulating 1/2; mTOR, mammalian target of rapamycin; p38 MAPK, p38 Mitogen‐activated protein kinase; PPARγ, peroxisome proliferator activated receptor gamma; PGC‐1α, PPARG coactivator 1 alpha; Pre‐SREBP, premature SREBP; SREBP, sterol regulatory element binding protein; TEAD, TEA domain transcription factor; YAP/TAZ, Yes1‐associated transcriptional regulator/Tafazzin.

FIGURE 3

Microenvironment‐mediated lipid metabolic reprogramming in cancer. Acidic pH in the TME contributes to enhanced cholesterol and FA synthesis in cancer cells. Lipocytes can activate AMPK to facilitate FAO in tumor cells. In addition, enhanced lipolysis by lipocytes generates lipid droplets that can be absorbed by cancer cells. CAFs also show enhanced lipolysis that helps fuel cancer cells with lipid droplets. Leptin in the TME and TH‐17‐secreted IL‐17 can promote FA uptake and FAO via activation of STAT3 signaling. Epithelial cells can increase the level of PUFA and glycerophosholipid in cancer cells Abbreviations: AMPK, adenosine 5‘‐monophosphate (AMP)‐activated protein kinase; ACC, acetyl‐CoA carboxylase; CAF, cancer‐associated fibroblast; FATP1, fatty acid transport protein 1; STAT3, signal transducer and activator of transcription 3.

FIGURE 4

Lipid metabolism reprogramming influences tumor immunogenicity. Increased FA synthesis in cancer cells contributes to lipid storage in TME, which fuels FAO in Treg cells. SCFA can also promote the development of Treg cells via inducing Foxp3 expression. Cancer cell‐secreted PGE2 can suppress NK cell cytotoxicity and NK cell differentiation. PGE2 can also lead to increased expression of PD1 in CTL and increased expression of PD‐L1 in MDSC. PGE2 can inhibit NK cell function and promote the polarization of macrophages to M2 macrophages. PGE2‐secreted by mammary gland tumor cells can also the activate EP2 and EP4 receptors in DCs to stimulate the generation of IL‐23, a critical cytokine for Th17 cell survival and expansion. Oxysterol from cancer cells can inhibit T cell antitumor immunity via induction of immune check point expression and T cell exhaustion. Oxysterol may activate LXR to decrease the expression of CCR7 on the DC surface, preventing their migration to secondary lymphatics and thus reducing potential antigen presentation. Oxysterol can interact with CXCR2 to recruit MDSC into the TME Abbreviations: CCR7, C‐C motif chemokine receptor 7; CXCR2, C‐X‐C motif chemokine receptor 2; DC, dendritic cells; EP2/4, prostaglandin E receptor 2/4; ER, endoplasmic reticulum; FA, fatty acid; FABP5, fatty acid binding protein 5; FAO, fatty acid oxidation; FAS, fatty acid synthesis; Foxp3, forkhead box P3; LXR, liver X receptor; MDSC, myeloid‐derived suppressor cells; NK cell, natural killer cell; PD1, programmed cell death 1; PDL1, programmed cell death 1 ligand 1; PGE2, prostaglandin E2; PUFA, polyunsaturated fatty acid; Th17, T helper cell 17.