Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer

Abstract

Previously regarded as simple fat storage particles, new evidence suggests that lipid droplets (LDs) are dynamic and functional organelles involved in key cellular processes such as membrane biosynthesis, lipid metabolism, cell signalling and inflammation. Indeed, an increased LD content is one of the most apparent features resulting from lipid metabolism reprogramming necessary to support the basic functions of cancer cells. LDs have been associated to different cellular processes involved in cancer progression and aggressiveness, such as tumorigenicity, invasion and metastasis, as well as chemoresistance. Interestingly, all of these processes are controlled by a subpopulation of highly aggressive tumoral cells named cancer stem cells (CSCs), suggesting that LDs may be fundamental elements for stemness in cancer. Considering the key role of CSCs on chemoresistance and disease relapse, main factors of therapy failure, the design of novel therapeutic approaches targeting these cells may be the only chance for long-term survival in cancer patients. In this sense, their biology and functional properties render LDs excellent candidates for target discovery and design of combined therapeutic strategies. In this review, we summarise the current knowledge identifying LDs and CSCs as main contributors to cancer aggressiveness, metastasis and chemoresistance.

Keywords: Cancer stem cells; Chemoresistance; Lipid droplets; Lipid metabolism; Lipids; Stemness.

Figure 1

Structure and cellular functions of lipid droplets. Lipid droplets (LDs) have a hydrophobic core of neutral lipids, mainly cholesteryl esters and triglycerides surrounded by a monolayer of phospholipids. LDs are coated with peripheral and integral proteins such as cell death-inducing DFF45-like effector and perilipins proteins, and lipid metabolism enzymes implicated in lipid synthesis and lipolysis: diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2), acyl-CoA cholesterol acyltransferases 1 and 2 (ACAT1 and ACAT2), adipose triglyceride lipase, hormone-sensitive lipase and monoacylglycerol lipase. LDs play roles in energy supply, via fatty acid oxidation, and signalling, by producing lipid intermediates that include pro- and anti-inflammatory signalling molecules and peroxisome proliferator-activated (PPAR) ligands. Upon activation, PPARs together with the coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha form a nuclear complex with RXR that binds to the DNA to activate the transcription of target genes. TAG: Triglycerides; CIDE: Cell death-inducing DFF45-like effector; PLIN: Perilipins; ATGL: Adipose triglyceride lipase; HSL: Hormone-sensitive lipase; MAGL: Monoacylglycerol lipase; FA: Fatty acid; CE: Cholesteryl esters; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; DGAT: Diacylglycerol acyltransferases; ACAT: Acyl-CoA cholesterol acyltransferases; PPARs: Peroxisome proliferator-activated receptors.

Figure 2

Features of cells with high content of lipid droplets. Cells with high lipid droplets (LD) content show activation of different signalling pathways such as Wnt/β-catenin, Hippo/Yes-associated protein, Notch, Hedgehog and PPARs/PGC-1α. Increased LD content has been linked to aggressive phenotypes in tumour cells, such as stemness, tumorigenicity, migration and invasion, metabolic plasticity and chemoresistance. LD: Lipid droplets; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPARs: Peroxisome proliferator-activated receptors; YAP: Yes-associated protein.