Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development
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...2).12,13 This is largely achieved through β-oxidation of stored lipids, leading to the production of acetyl-CoA through oxidative degradation of FAs.14,15 The acetylCoA produced from each round of β-oxidation can subsequently enter the tricarboxylic acid (TCA) cycle to generate NADH and FADH2 for the electron transport chain, ultimately leading to the synthesis of approximately six times more ATP than oxidation of carbohydrates.14 Moreover, the oxidation of citrate derived from acetyl-CoA by isocitrate dehydrogenase 1 (IDH1) is one of the main sources of cellular NADPH production.16 Thus, β-oxidation of LDs provides sufficient ATP to fuel the metastatic cascade, and generates NADPH that is essential for anabolic metabolism and detoxification of reactive oxygen species (ROS).17–20 This is particularly relevant for hypoxic cells, which have elevated FA uptake and accumulation of LDs following hypoxia-inducible factor (HIF)-1α-dependent expression of FABP3 and FABP7....
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...With regard to acetyl-CoA metabolism, tumours specifically upregulate ACSS2 under conditions of hypoxia or lipid deprivation, leading to increased acetate uptake and ligation with CoA to produce acetyl-CoA for de novo lipogenesis.33 Importantly, a HIF–SREBF2 signalling axis drives ACSS2 expression and confers exquisite sensitivity to its inhibition in hypoxic or otherwise metabolically stressed tumours.33 Although the development of ACSS2-specific inhibitors is lagging considerably behind ACLY-targeted therapies, efforts are being made to bridge this gap through identification of novel selective inhibitors by using high-throughput screens.217 In fact, one of the most potent compounds identified, N-(2,3-di-2-thienyl-6quinoxalinyl)-N'-(2-methoxyethyl)urea, has already been shown to sensitise chemotherapy-resistant bladder cancers that are dependent on acetate metabolism to cisplatin.217,218 Targeting SCD: inhibiting fatty acid desaturation Desaturation of FAs by SCD enzymes produces monounsaturated FAs that contribute to the synthesis of additional lipid species including glycerophospholipids and sphingolipids.56 Ectopic SCD expression promotes EMT and is associated with poor prognosis in breast and colorectal cancer.56 This provides a therapeutic opportunity for tumours that depend on canonical SCDmediated desaturation, and the effect is more apparent in the absence of exogenous lipids.55 SCD inhibitors, such as SSI-4, betulinic acid (BetA) and MF-438, have been shown to induce apoptosis in cancer cells through multiple mechanisms including induction of the ER-stress response, modulating mitochondrial dynamics by altering cardiolipin structure, and growth inhibition of cancer stem cells (Table 1).55,56,219–221 Interestingly, not all cancers display sensitivity to SCD inhibition, as they rely on a compensatory desaturation pathway by utilising FADS2 to generate sapienate from palmitate.57 In this context, sapienate, instead of palmitoleate generated from SCD, contributes substantially to membrane synthesis in hepatocellular and lung carcinomas.57 As a result, a significant reduction in tumour area is only observed following combinatorial treatment of hepatocellular carcinoma xenografts with SCD and FADS2 inhibitors, thereby blocking any compensatory pathways for obtaining desaturated FAs.57 In light of these findings, it is important to consider that the canonical function of FADS2 is the desaturation of LA to γ-linolenic acid (C18:3n6).180 Given that FADS2 is obligatory for the de novo synthesis of long-chain omega-6 FAs including AA, it would be interesting to further investigate the potential regulatory mechanisms and microenvironmental conditions that determine the substrate preference of FADS2....
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...Hyperinsulinaemia activates the insulin receptor and PI3K signalling, contributing to increased CD36 membrane translocation and uptake of exogenous FAs.116 At the onset of insulin resistance, GLUT4 expression and translocation is inhibited, leading to increased blood glucose levels, decreased glycolysis and high FA β-oxidation of intracellular lipid pools.117 In terms of specific mechanisms, the accumulation of FAs in response to insulin resistance may drive DAG synthesis, which can activate conventional PKC isoforms, leading to the phosphorylation of insulin receptor substrate 1 (IRS1) and consequent inhibition of PI3K–AKT signalling.118 Moreover, dysregulated lipid signalling could induce a negative-feedback loop initiated by the activation of mTORC1–p70S6K and its subsequent phosphorylation-induced inhibition of IRS1....
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...For instance, FABP4 is a transcriptional target of HIF1α that facilitates extracellular scavenging of long-chain unsaturated lysophospholipids, including LPCs, lysophosphatidylethanolamines (LPEs) and lysophosphatidylglycerols (LPGs) that can be used as a nutrient source under conditions of metabolic stress.27,28 Interestingly, this phenotype of increased FA scavenging is also recapitulated under normoxic conditions following oncogenic Ras activation, and is accompanied by reduced oxygen consumption, elevated citrate synthesis from reductive carboxylation and a consequent independence from SCD-1 to derive unsaturated FAs.27 Taken together, these results demonstrate that whilst changes in the microenvironment conditions or oncogenic activation of signalling pathways confer resistance to SCD-1 inhibitors, they might open novel opportunities for therapy by increasing the reliance of cancer cells on FA uptake....
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...De novo lipogenesis allows for the synthesis of a diverse group of fatty acids De novo lipogenesis is the process through which carbon atoms derived from carbohydrates such as glucose and amino acids including glutamine are converted into FAs.(29) In normal tissue, de novo lipogenesis is restricted to hepatocytes and adipocytes; however, cancer cells may also reactivate this anabolic pathway even in the presence of exogenous lipid sources....
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...Cancer Cell 27, 57–71, January 12, 2015 ª2015 The Authors 57 for biomass production required for growth and survival under unfavorable conditions (Baenke et al., 2013)....
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...for biomass production required for growth and survival under unfavorable conditions (Baenke et al., 2013)....
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References
4,927 citations
"Hooked on fat: the role of lipid sy..." refers background in this paper
...PIP3 is also the substrate for phosphatase and tensin homologue (PTEN), and PTEN is one of the genes that is most frequently mutated or deleted in cancer (Li et al., 1997; Steck et al., 1997)....
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3,486 citations
"Hooked on fat: the role of lipid sy..." refers background in this paper
...Together with the environmental conditions created by the expanding cell mass, stromal cells constitute an important component of the tumorigenic microenvironment in which cancer cells exist (Hanahan and Coussens, 2012)....
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3,332 citations
"Hooked on fat: the role of lipid sy..." refers background in this paper
...In contrast, M2 macrophages generally promote tumour growth by inducing cancer cell invasion, angiogenesis and metastasis formation (Joyce and Pollard, 2009)....
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...Tumour growth is also strongly affected by the complex interactions between cancer cells and stromal components (Joyce and Pollard, 2009), including cancer-associated fibroblasts (CAFs), macrophages and other immune cells (Fig....
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...Tumour-stromal interactions Tumour growth is also strongly affected by the complex interactions between cancer cells and stromal components (Joyce and Pollard, 2009), including cancer-associated fibroblasts (CAFs), macrophages and other immune cells (Fig....
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3,091 citations
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...This mode of mobilisation of lipids from intracellular stores has consequently been termed ‘macrolipophagy’ (Singh et al., 2009)....
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...Interestingly, the release of lipids from lipid droplets in response to nutrient starvation requires components of the autophagic machinery, including Atg5, and inhibition of autophagy results in lipid droplet accumulation (Singh et al., 2009)....
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3,064 citations
"Hooked on fat: the role of lipid sy..." refers background in this paper
...…coordinated activation of several processes: cell polarisation and elongation, formation of cell protrusions and attachment to components of the ECM, and contraction of the cell body to generate a force for the movement of the cell body in the direction of the leading edge (Friedl and Wolf, 2003)....
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...Cancer cell migration Directed cell migration requires the coordinated activation of several processes: cell polarisation and elongation, formation of cell protrusions and attachment to components of the ECM, and contraction of the cell body to generate a force for the movement of the cell body in the direction of the leading edge (Friedl and Wolf, 2003)....
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