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. 2019 Dec 10;7(3):258–270. doi: 10.1016/j.ajur.2019.12.003

Figure 1.

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.