Lipogenic effects of androgen signaling in normal and malignant prostate

Abstract

Prostate cancer is an androgen-dependent cancer with unique metabolic features compared to many other solid tumors, and typically does not exhibit the "Warburg effect". During malignant transformation, an early metabolic switch diverts the dependence of normal prostate cells on aerobic glycolysis for the synthesis of and secretion of citrate towards a more energetically favorable metabolic phenotype, whereby citrate is actively oxidised for energy and biosynthetic processes (i.e. de novo lipogenesis). It is now clear that lipid metabolism is one of the key androgen-regulated processes in prostate cells and alterations in lipid metabolism are a hallmark of prostate cancer, whereby increased de novo lipogenesis accompanied by overexpression of lipid metabolic genes are characteristic of primary and advanced disease. Despite recent advances in our understanding of altered lipid metabolism in prostate tumorigenesis and cancer progression, the intermediary metabolism of the normal prostate and its relationship to androgen signaling remains poorly understood. In this review, we discuss the fundamental metabolic relationships that are distinctive in normal versus malignant prostate tissues, and the role of androgens in the regulation of lipid metabolism at different stages of prostate tumorigenesis.

Keywords: Androgen receptor; Fatty acids; Metabolism; Phospholipids; Prostate gland.

Figure 1

Metabolic landscape of prostate cancer progression (from normal prostate to malignant to metastatic/CRPC). Normal prostate epithelial cells exhibit high rates of aerobic glycolysis and low rates of oxidative phosphorylation. Glucose is used for citrate production and secretion, resulting in an impaired TCA cycle; this process is facilitated by zinc and aspartate through inhibition of m-aconitase and supply of metabolic precursors (i.e. oxaloacetate). Alternatively, citrate may be used for lipid biosynthesis through androgen-mediated activation of lipogenic enzymes. During malignant transformation, prostate cancer cells exhibit increased oxidative phosphorylation and hence, reactivate the TCA cycle to oxidize citrate for energy production. Instead of glucose, FFAs are the dominant bioenergetic substrates that feed into the TCA cycle for energy production. More importantly, de novo lipogenesis is enhanced at this stage of disease through the up-regulation of AR-regulated lipogenic enzymes. Despite initial positive responses to androgen-deprivation therapy, patients eventually progress to CRPC. AR signalling is maintained in CRPC; AR resistant mechanisms such as the AR-variants (AR-Vs) and/or indirect activation of alternative metabolic pathways (i.e. SREBP) play a role in driving the androgen-mediated lipogenic phenotype that may contribute to prostate cancer progression and treatment resistance. Notably, increased aerobic glycolysis or the Warburg effect is observed in advanced stages of the disease/CRPC. Words highlighted in red: AR-regulated genes. Thin/dotted lines: Baseline level; thick lines: Up-regulated. TCA, tricarboxylic acid cycle; PDH, pyruvate dehydrogenase; MAAT, aspartate aminotransferase; FASN, fatty acid biosynthesis; ACC, acetyl-CoA-carboxylase; SCD, stearoyl-CoA-desaturase; OXPHOS, oxidative phosphorylation; CRPC, castrate-resistant prostate cancer; AR, androgen receptor; FFAs, lipids or free fatty acids; MDH, malate dehydrogenase; α-KG, alpha ketoglutarate; AR-Vs, androgen receptor variants; CPT1, carnitine palmitoyltransferase 1; FAS, fatty acid synthesis. Created with BioRender.com.

Figure 2

Overview of lipid metabolism in prostate cancer. Androgens regulate a number of lipid metabolic pathways in prostate cancer cells, including lipid uptake, biosynthesis and degradation. The AR directly (via binding of AR to the ARE) or indirectly (via activation of SREBP) regulates key lipid metabolic genes. Lipids can be derived from lipolysis of adipocytes or from circulating lipoproteins (LDL, HDL, VLDL). Alternatively, lipids can be synthesized endogenously by the cells via enzymes ACC and FASN. Androgens up-regulate lipid transporters that transport lipids or free fatty acids to the mitochondria for fatty acid oxidation (β-oxidation) or de novo lipogenesis. Free fatty acids are shuttled into the mitochondria as Acyl-CoAs by coupling with CPT1 (a mitochondrial transporter); a cyclical series of reactions result in the shortening of Acyl-CoA and the production of energy in the form of ATP via the TCA cycle. Citrate produced from the TCA cycle may also be cleaved to produce Acetyl-CoA, which is a precursor for de novo lipogenesis in the cytosol. Synthesized fatty acids may be further modified (i.e. degree of saturation via SCD) to generate a variety of lipids such as phospholipids that compose the plasma membranes, to promote lipid droplet production or to act as oncogenic signalling molecules to drive disease progression. Words in red = androgen-regulated genes. ARE, androgen response element; SRE, SREBP response element; AR, androgen receptor; LDL, low density lipoprotein; HDL, high density lipoprotein; VLDL, very low density lipoprotein; FASN, fatty acid biosynthesis; TCA, tricarboxylic acid cycle; SCD, stearoyl-CoA-desaturase; SREBP, sterol response element binding protein. Created with BioRender.com.