Lipid metabolism reprogramming and its potential targets in cancer

Abstract

Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Increased lipid uptake, storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. Lipids constitute the basic structure of membranes and also function as signaling molecules and energy sources. Sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors in the endoplasmic reticulum, play a central role in the regulation of lipid metabolism. Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth. SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor, thus linking glucose metabolism and de novo lipid synthesis. Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.

Keywords: Cancer; Cholesterol; Fatty acids; Lipid droplets; Lipid metabolism; SCAP; SREBPs.

Fig. 1

Regulation of lipid metabolism in cancer cells. In cancer cells, glucose uptake and glycolysis are markedly up-regulated by RTKs via the PI3K/Akt/mTOR signaling pathway, generating large amounts of pyruvate. Pyruvate is converted to lactate and it also enters the mitochondria, where it forms citrate, which is transported by SLC25A1 from the mitochondria into the cytoplasm, where the citrate serves as a precursor for de novo synthesis of fatty acids and cholesterol. Glutamine can also enter into mitochondria and participate in energy production and lipid synthesis. Acetate is converted to acetyl-CoA by the ACSS2 enzyme, serving as another source of lipid synthesis. Glucose participates in the HBP to form glycans that will be added to proteins during glycosylation. Oncogenic EGFR signaling increases N-glycosylation of SCAP, which activates SREBP-1 and -2 [55, 58], which ultimately up-regulate expression of enzymes in lipogenesis pathways and expression of LDLR. The enzyme up-regulation promotes fatty acid and cholesterol synthesis, while the LDLR up-regulation increases cholesterol uptake [40]. The microRNA miRNA-29 regulates the SCAP/SREBP pathway via a novel negative feedback loop [101]. The transporter CD36 brings fatty acids into cancer cells. When cellular fatty acids and cholesterol are in excess, they can be converted to TG and CE by the enzymes DGAT1/2 and SOAT1/ACAT1, forming LDs. When present in excess, cholesterol can be converted to 22- or 27-hydroxycholesterol, which activate LXR to up-regulate ABCA1 expression, promoting cholesterol efflux. ABCA1 ATP-binding cassette transporters A, ACC acetyl-CoA carboxylase, ACLY ATP citrate lyase, ACSS2 acetyl-CoA synthetase 2, DGAT1/2 diacylglycerol O-acyltransferase 1/2, FAs fatty acids, FASN fatty acid synthase, HBP hexosamine biosynthesis pathway, HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCS 3-hydroxy-3-methylglutaryl-CoA synthase, LD lipid droplet, LDLR low-density lipoprotein receptor, LXR liver X receptor, RTKs oncogenic tyrosine kinase receptors, SCAP SREBP cleavage-activating protein, SCD1 stearoyl-CoA desaturase 1, SLC25A1 solute carrier family 25 member 1, SOAT1 (also known as ACAT1) sterol O-acyltransferase, SREBPs sterol regulatory element-binding proteins, TG/CE triglycerides/cholesteryl esters

Fig. 2

SCAP N-glycosylation is essential for SREBP trafficking and activation. SREBP activation is repressed by the ER-resident protein Insig, which binds to SCAP to prevent SREBP translocation and nuclear activation. The Nobel Prize-winning laboratories of Brown and Goldstein revealed that sterols modulate Insig interaction with SCAP to retain the SCAP/SREBP complex in the ER and inhibit SREBP [273, 274]. Our recent work has shown that glucose-mediated N-glycosylation stabilizes SCAP and promotes its dissociation from Insig, triggering the trafficking of the SCAP/SREBP complex from the ER to the Golgi, where SREBPs are cleaved to release their transcriptionally active N-terminal fragments to activate lipogenesis for tumor growth [55]. We further showed that EGFR signaling enhances glucose intake and thereby promotes SCAP N-glycosylation and SREBP activation