Progress in therapeutic strategies based on cancer lipid metabolism.

Lipids are widely distributed in cellular organelles and comprise thousands of different types of molecules, including fatty acids, phospholipids, triglycerides, sphingolipids, cholesterol, etc. Normal cells acquire lipids through de novo synthesis and uptake. In order to satisfy the demands of growth and proliferation, cancer cells must rewire their metabolism,1, 2 especially lipid metabolism.3 Indeed, lipid synthesis is strongly upregulated in cancers to satisfy the demands of increased membrane biogenesis4 and even acquire therapeutic resistance.5 Lipid uptake and storage are also elevated in cancer cells.6, 7 Targeting lipid metabolism has become a novel anti‐cancer strategy.

Past strategy: Blocking lipid synthesis

Accumulating evidence has demonstrated that increased de novo fatty acid (FA) synthesis is a hallmark of cancer.3, 8 The expression levels of enzymes responsible for FA synthesis are usually upregulated in many types of cancer.9, 10 Previous studies revealed that pharmacologically inhibition of the key enzymes of FA synthesis decreases cancer cell proliferation.11, 12 Fatty acid synthase (FASN) was the first molecular discovery linking lipid metabolism to cancer.13 Many studies have since shown increased FASN expression in various cancers,14 while inhibiting FASN by its inhibitors, such as TVB‐3166 and C93, significantly reduces FA synthesis and suppresses tumor growth in the xenograft models of lung cancer.15, 16 Additionally, the acetyl‐CoA carboxylase (ACC) catalyzes ATP‐dependent carboxylation of acetyl‐CoA, generating malonyl‐CoA for fatty acid synthesis following the conversion of citrate and acetate to acetyl‐CoA. The ACC inhibitors TOFA, soraphen A and ND646 have also shown significant anti‐tumor effects in xenograft models of lung and breast cancer.17, 18, 19 ATP citrate lyase (ACLY) converts cytoplasmic citrate to acetyl‐CoA, a precursor of lipid synthesis and a substrate for protein acetylation. Inhibiting ACLY at the genetic level or pharmacologically significantly suppresses tumor growth.20, 21

Current progress: Blocking lipid uptake, intracellular lipolysis and utilization of lipids

Recent studies have shown that blocking lipid uptake, intracellular lipolysis and utilization of lipids are potential approaches to inhibit tumor growth. Compared to normal cell, cancer cells require more lipids than normal cells, therefore, they obtain lipids by upregulating cell surface receptors for plasma lipids.3 Cluster of differentiation 36 (CD36) is a cell surface receptor that facilitates lipid uptake.22 It has been established as a functional driver of metastasis in a lipid metabolism‐dependent manner.23 In addition, the uptake of extracellular fatty acids in breast cancer and glioblastoma cell lines is promoted under hypoxia via the upregulation of heart‐type fatty‐acid‐binding protein 3 and 7 (FABP3 and FABP7), thereby leading to elevated lipid droplet (LD) formation.24 These findings expand our knowledge of lipid metabolism in cancer progression and add promising new targets for the development of novel anti‐cancer therapeutics.

Cytoplasmic fatty acids are usually stored as triglycerides (TGs) in LDs and are released through intracellular lipolysis.11, 25 Adipose triglyceride lipase (ATGL)26, 27 and monoacyl glycerol lipase (MAGL)28 provide a stream of intracellular free FA that play important and critical roles in cancer cells proliferation and tumor progression by de‐esterification. Therefore, inhibiting intracellular lipolysis shows promise as a therapeutic strategy for cancer.

Abundant lipids in cancer cells provide essential substrates for signaling molecules, and mitochondrial oxidative metabolic fuels to support the rapid growth and proliferation of cancer cells.29, 30 Signaling lipids, for example, phosphoinositides, eicosanoids and sphingolipids, control important cellular processes and dysfunction of their metabolism has been implicated in cancer.31 As the critical roles of lipid signaling pathways in cancer have been established, compounds targeting lipid signaling pathways, such as Rapamycin,32 Curcumin,33 Tetracycline,34 ICI182780,35 etc., are becoming available for clinical use. Lipids also supply energy to cancer cells through fatty acid β‐oxidation. Oxidative mitochondrial pathways such as fatty acid β‐oxidation and oxidative phosphorylation (OXPHOS) have been implicated in cancer cell survival, and inhibiting fatty acid β‐oxidation reduces the tumor‐initiating potential.36 This evidence suggests the possibility of the fatty acid β‐oxidation pathway as a potential therapeutic target for cancer.

Future perspectives: Blocking lipid storage while limiting lipid synthesis and utilization

In addition to limiting lipid synthesis and utilization, how to block lipid storage is the future therapeutic direction in cancer. LDs are key organelles that function as storage of cellular surplus of lipid molecules in esterified form. Cancer cells contain more lipid droplets than normal cells. The upregulation of LD‐decorating proteins, such as hypoxia‐inducible protein 2 (HIG2), Perilipin, adipose differentiation‐related protein (ADRP) and Tip47 exhibited in multiple cancer cells have been shown to promote formation and accumulation of LDs.37 Moreover, Savkovic and colleagues reported that stimulation of LD density promoted proliferation in colon cancer, whereas silencing perilipin 2 (PLIN2) or overexpression of forkhead box O3 (FOXO3) inhibited proliferation. Thus, they suggested that FOXO3 and LDs might serve as new targets for therapeutic intervention of colon cancer.38 Furthermore, Penrose et al. demonstrated that LD‐depletion, through the inhibition of lipid synthesis or silencing of PLIN2, significantly attenuated proliferation of colon cancer cells.39 These studies support LD‐associated proteins as potential targets for cancer treatment. However, the molecular mechanisms underlying LD‐associated stress responses need to be further elucidated.