The fat side of prostate cancer

Abstract

Prostate cancer (PCa) metabolism appears to be unique in comparison with other types of solid cancers. Normal prostate cells mainly rely on glucose oxidation to provide precursors for the synthesis and secretion of citrate, resulting in an incomplete Krebs cycle and minimal oxidative phosphorylation for energy production. In contrast, during transformation, PCa cells no longer secrete citrate and they reactivate the Krebs cycle as energy source. Moreover, primary PCas do not show increased aerobic glycolysis and therefore they are not efficiently detectable with (18)F-FDG-PET. However, increased de novo lipid synthesis, strictly intertwined with deregulation in classical oncogenes and oncosuppressors, is an early event of the disease. Up-regulation and increased activity of lipogenic enzymes (including fatty acid synthase and choline kinase) occurs throughout PCa carcinogenesis and correlates with worse prognosis and poor survival. Thus, lipid precursors such as acetate and choline have been successfully used as alternative tracers for PET imaging. Lipid synthesis intermediates and FA catabolism also emerged as important players in PCa maintenance. Finally, epidemiologic studies suggested that systemic metabolic disorders including obesity, metabolic syndrome, and diabetes as well as hypercaloric and fat-rich diets might increase the risk of PCa. However, how metabolic disorders contribute to PCa development and whether dietary lipids and de novo lipids synthesized intra-tumor are differentially metabolized still remains unclear. In this review, we examine the switch in lipid metabolism supporting the development and progression of PCa and we discuss how we can exploit its lipogenic nature for therapeutic and diagnostic purposes. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

Keywords: Fatty acids; Imaging; Lipid metabolism; Metabolic diseases; Prostate cancer.

Figure 1. The role of lipids in PCa cells

Lipids exert several biological functions in cancer cells, including energy supply and storage, membrane building blocks, signaling molecules, protein post-translation modifications, substrates for steroids to support PCa cells survival, proliferation, migration, and invasion. PI, phosphatidylinositol, PA, phopshatidic acid; DAG, diacylglycerol; LPA, lysophosphatidic acid; PC, phosphocholine; PS, Phosphatidylserine; PE, Phosphatidylethanolamine; GPI, Glycosylphosphatidylinositol.

Figure 2. Increased de novo lipogenesis in PCa

Citrate generate in TCA cycle is exported to the cytosol to fuel the mevalonate and fatty acid (FA) synthesis pathways by conversion to acetyl-CoA by ATP citrate lyase (ACLY). Acetyl-CoA acetyltransferases (ACAT) is the first enzyme of cholesterol synthesis pathway that converts acetyl-CoA into acetoacetyl-CoA, which functions as a substrate for the synthesis of mevalonate by HMG-CoA synthase (HMGCS), followed by the reductase (HMGCR). The latter is the rate-limiting step for the production of cholesterol, which is the precursor to androgens. Acetyl-CoA carboxylase 1 (ACC) initiates the first committed step to FA synthesis to produce malonyl-CoA. Seven malonyl-CoA molecules are added to acetyl-CoA by fatty acid synthase (FASN) to produce palmitic acid, a 16-carbon saturated FA (SFA). Palmitic acid can be further elongated to form long SFAs and/or desaturated by stearoyl-CoA desaturase 1 (SCD1) and by other desaturases to produce monounsaturated FA (MUFAs). The reducing factor nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for FA synthesis, is provided by pentose phosphate pathway (PPP), by malic enzyme (ME1), which produces pyruvate from malate (shunt malate-pyruvate), and by cytosolic isocitrate dehydrogenase (IDH1) to produce α-ketoglutarate (αKG) from isocitrate (shunt isocitrate αKG). TAG, triacylglycerols; PL, phospholipids; CYP11A1, p450, family 11, subfamily A, polypeptide 1; CYP17A1; p450, family 11, subfamily A, polypeptide 1; 3β-HSD1, 2, 3-β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase 1, 2; 17β-HSD, 17β-Hydroxysteroid dehydrogenase; SRD5A 1, 2, steroid-5α-reductase 1, 2.

Figure 3. Regulation of lipid metabolism by oncogenes and tumor suppressors

PCa cancer cells show high rates of de novo lipid synthesis and the enzymes belonging to the pathway are regulated by oncogenic signals. Growth factor-activated PI3K-Akt or hypoxia-induced HIF stimulates glucose uptake and hexokinases to promote glycolysis, providing more synthetic precursors for FA synthesis. Akt also activates the lipogenic enzyme activity and expression through direct phosphorylation or SREBP-mediated transcription of lipogenic genes. Activation of E2F following loss of the retinoblastoma (Rb) protein increases expression of SREBPs and their target genes. The tumor suppressor p53 plays a role in glucose uptake, pentose phosphate pathway, transcription of lipogenic genes, and anaplerosis of citrate. Mutant p53 (p53mut) also increases the expression of genes within the cholesterol biosynthesis (mevalonate). The tumor suppressor LKB1-AMPK axis, activated in response to low cellular energy levels, inhibits de novo lipogenesis through direct inhibition of ACC and SREBP-1. Myc promotes citrate anaplerosis through increasing glutamine transporters and glutaminase 2 expression. The activity and expression of lipogenic enzyme, ACLY, ACC, and FASN are also regulated at multiple levels through mTORC1 and mitogen-activated protein kinases (MAPKs). IDH1, isocitrate dehydrogenase 1; pRB, retinoblastoma 1; Glut, Glucose transporter; FBP, Fructose-1,6-bisphosphate; PEP, phosphoenolpyruvate; HK, Hexokinase; G6PDH, Glucose-6-phosphate dehydrogenase; PFK, Phospho-fructokinase; PKM2, Tumor-specific pyruvate kinase M2; LDHA, Lactate dehydrogenase A; HIF, Hypoxia-inducible factor; AMPK, AMP-activated protein kinase; PI3K, Phosphatidylinositol 3-kinase; MAPK, Mitogen activated protein kinase; mTOR, Mammalian target of rapamycin; E2F, DNA-binding transcription factor; SREBP-1, Sterol-regulatory element-binding protein-1; TCA cycle, tricarboxylic acid cycle; OAA, Oxaloacetate; Mal, Malate; ME, Malic enzyme; αKG, α-ketoglutarate; ACLY, ATP citrate lyase; ACC, Acetyl-CoA carboxylase; FASN, Fatty acid synthase; HMGCR, HMG-CoA reductase; NADPH, Nicotinamide adenine dinucleotide phosphate; Glt, glutamate.

Figure 4. Drug-mediated targeting of lipogenic enzymes

A lot of efforts have been spent to identify inhibitors of de novo FA and cholesterol synthesis as well as inhibitors of intra-tumor de novo steroidogenesis to use in cancer therapy. In this diagram, inhibitors of FA and cholesterol synthesis are depicted in red and blue squares, respectively. The enzymes belonging to the two pathways are highlighted in corresponding red and blue colors. Novel small molecules targeting fatty acid synthase (FASN), AMP-activated protein kinase (AMPK), and intra-tumor synthesis of androgens have been recently developed, as discussed in the text. ACLY, ATP citrate lyase; ACC, Acetyl-CoA carboxylase; ACAT, Acetyl-CoA acetyltransferases; HMGCS, HMG-CoA synthase; HMGCR, HMG-CoA reductase; SCD1, stearoyl-CoA desaturase 1; CYP11A1, p450, family 11, subfamily A, polypeptide 1; CYP17A1; p450, family 11, subfamily A, polypeptide 1; 3β-HSD1, 2, 3-β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase 1, 2; 17β-HSD, 17β-Hydroxysteroid dehydrogenase; SRD5A 1, 2, steroid-5α-reductase 1, 2.