Abnormal lipid synthesis as a therapeutic target for cancer stem cells

Abstract

Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.

Obesity and cancer stem cells: Roles in cancer initiation, progression and therapy resistance

“…Therefore, in addition to the abovementioned studies that investigated the regulation of CSC function by lipids as elements of a pro-obesity diet, numerous studies have explored the effects of lipids on CSCs at the cellular metabolism level. Metabolism of fatty acids and cholesterol, including de novo biosynthesis, storage and fatty acid oxidation (FAO), supports the stemness, proliferation and chemotherapy resistance of CSCs[ 57 ]. Metabolic analysis demonstrated that lipid synthesis, including de novo lipid biosynthesis, lipid desaturation, and cholesterol synthesis, displays high activity in CSCs, indicating that lipid synthesis plays critical roles in stemness maintenance[ 58 ].…”

“…FAO is also responsible for the stemness and chemotherapy resistance in gastric cancer induced by mesenchymal stem cells (MSCs)[ 61 ]. To meet the critical functions of lipids in CSCs, lipid droplets, organelles that store neutral lipids, accumulate and are more abundant in CSCs in numerous types of cancer[ 57 ]. Although evidence connecting lipid metabolism and CSCs is increasingly accumulating, whether obesity can augment the lipid metabolic alteration in CSCs is not clear because studies on the metabolic adaptations of CSCs in obese environments are limited.…”

Regulation of iron metabolism and ferroptosis in cancer stem cells

“…To maintain stemness characteristics and meet survival needs, CSCs adapt to lipid metabolism by upregulating de novo fatty acid synthesis, lipid uptake, lipid desaturation, oxidation, and lipid droplet synthesis, etc. ( 83 , 86 ). Phospholipids containing PUFAs are most susceptible to peroxidation during ferroptosis.…”

“…Fatty acid synthesis is more active in CSCs than in non-CSCs, and its key enzymes are expressed at higher levels in CSCs, such as ATP citrate lyase (ACLY), acetyl coenzyme A carboxylase (ACC), fatty acid synthase (FASN), and sterol regulatory element-binding protein (SREBP), which regulate the expression of these genes ( 86 ). FASN-mediated fatty acid synthesis promotes gemcitabine resistance in pancreatic cancer cells, whereas the FASN inhibitor, orlistat, reduces pancreatic cancer cell stemness ( 87 ).…”

LncRNAs‐circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers

“…Additionally, the mevalonate pathway (MVA) in cholesterol de novo biosynthesis is the only source of farnesyl-diphosphate and geranylgeranyl-diphosphate (GGPP), which is important for prenylation of RasGTPase superfamily, including Ras and Rho, and the Rho-dependent YAP/TAZ nuclear localization to facilitate stemness genes expression in CSCs. [194,195] For instance, Lnc30 has been identified to enhance the biosynthesis of cholesterol that is mediated by SQLE. This process then leads to the activation of the PI3K/Akt signaling and ultimately regulates the stemness of breast cancer stem cells (BCSC).…”