Emerging role of lipid metabolism alterations in Cancer stem cells

Abstract

Background: Cancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a small population of cancer cells with self-renewal and tumor-initiating properties. Unlike the bulk of tumor cells, CSCs or TICs are refractory to traditional therapy and are responsible for relapse or disease recurrence in cancer patients. Stem cells have distinct metabolic properties compared to differentiated cells, and metabolic rewiring contributes to self-renewal and stemness maintenance in CSCs.

Main body: Recent advances in metabolomic detection, particularly in hyperspectral-stimulated raman scattering microscopy, have expanded our knowledge of the contribution of lipid metabolism to the generation and maintenance of CSCs. Alterations in lipid uptake, de novo lipogenesis, lipid droplets, lipid desaturation, and fatty acid oxidation are all clearly implicated in CSCs regulation. Alterations on lipid metabolism not only satisfies the energy demands and biomass production of CSCs, but also contributes to the activation of several important oncogenic signaling pathways, including Wnt/β-catenin and Hippo/YAP signaling. In this review, we summarize the current progress in this attractive field and describe some recent therapeutic agents specifically targeting CSCs based on their modulation of lipid metabolism.

Conclusion: Increased reliance on lipid metabolism makes it a promising therapeutic strategy to eliminate CSCs. Targeting key players of fatty acids metabolism shows promising to anti-CSCs and tumor prevention effects.

Keywords: Cancer stem cells; Fatty acid oxidation; Lipid desaturation; Lipid droplets; Lipid metabolism; Metabolomics; de novo lipogenesis.

Fig. 1

Alterations in lipid metabolism in CSCs. Both lipid catabolism and anabolism alterations contribute to stemness acquisition in CSCs, including lipid uptake, de novo lipogenesis, lipid desaturation, lipolysis, lipophagy, and FAO. Extracellular FFAs are transported into cells via CD36 and then reused via β-oxidation in mitochondria to release acetyl-CoA. Acetyl-CoA is converted to citrate by citrate synthase and then enters the Krebs cycle for complete oxidation. Alternatively, de novo fatty acids synthesis starts with acetyl-CoA and builds up by the addition of two-carbon units. In addition to lipid catabolism, fatty acids are esterified to glycerol and then triglycerides are stored in lipid droplets. Breakdown of lipids droplets via lipolysis or lipophagy enables stored energy mobilization to the mitochondria. Additionally, saturated fatty acids are desaturated into mono-unsaturated fatty acids by SCD1. Alterations in lipid metabolism not only satisfy energy demands for CSCs proliferation, but also provide essential components for biosynthetic pathways and redox homeostasis. ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; FASN, fatty acid synthase; CD36, cluster of differentiation 36; FAs, fatty acids; MUFAs, mono-unsaturated fatty acids; SCD1, stearoyl-CoA desaturase 1; CPT1, carnitine palmitoyltransferase 1; TCA cycle, tricarboxylic acid cycle; FAO, fatty acid oxidation; and LD, lipid droplet

Fig. 2

NANOG mediated metabolic reprogramming contributes to CSCs self-renewal and chemoresistance. NANOG binding on FAO genes(Acadvl, Echs1, and Acads) promoters stimulates it’s transcription but exerts opposite effect on OXPHOS genes(Cox6a2 and Cox15) transcription, leading to metabolic switch from OXPHOS to FAO and less ROS production in CSCs/TICs. NANOG also promotes lipid desaturation via up-regulating SCD1 expression. OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation

Fig. 3

Regulation of SREBP1 and lipid metabolism by oncogenic signaling in CSCs. Oncogenic PI3K (H1047R)- and K-Ras (G12 V) activates SREBP1 and SREBP2 to support de novo lipid synthesis and cell growth. The mTOR signaling regulates SREBP1 level through both transcriptional or translational mechanisms. Activation of PI3K.AKT/mTOR signaling pathway or FGFR3 leads to stabilization of SREBP1 protein and promotes SREBP1 translocation to nucleus. Mitotic kinase Cdk1 and Plk1 physically interact with nuclear SREBP1 protein. Sequentially phosphorylation of SREBP1 by Cdk1 and Plk1 blocks binding between the ubiquitin ligase Fbw7 and SREBP1 and attenuates SREBP1 degradation. Upon EGFR signaling activation, the nuclear form of PKM2 physically interacts with SREBP1, activating SREBP target gene expression and lipid biosynthesis

Fig. 4

Interaction between oncogenic signaling and lipid desaturation in CSCs. Oncogenic activation of K-RAS, PI3K/AKT/mTOR signaling stimulates de novo lipogenesis via upregulation of SREBP1. Increase of SCD1 expression and lipid desaturation by NANOG or oncogenic signaling in CSCs or TICs reciprocally amplify NF-κB, Wnt/β-catenin, and Yap activation. Activation of JAK/STAT3 promotes CPT1B expression and activates the FAO pathway, which in turn contributes to Src oncoprotein activation. SREBP1, sterol regulatory element-binding protein-1