Fig. 1: Schematic overview of the metabolic rewiring occurring in prostate epithelial cells during the different stages of cancer progression.

a Healthy prostate luminal cells accumulate high levels of zinc (due to the overexpression of its transporter), leading to the inhibition of mitochondrial aconitase, the key enzyme responsible for the citrate-isocitrate conversion in the TCA cycle. This inhibition results in the truncation of the TCA cycle and citrate accumulation and secretion. As a result, normal prostate epithelial cells are characterized by an inefficient OXPHOS. b In prostate cancer cells, intracellular zinc levels are significantly reduced (due to a decreased expression of its transporter); this leads to the reactivation of aconitase, restoring the citrate-isocitrate conversion, and consequently of the TCA cycle and OXPHOS metabolic pathways. In addition, both the hexosamine biosynthesis pathway (HBP) resulting in glycosylation and the pentose phosphate pathway (PPP) that generates NADPH and nucleotides are upregulated in PCa cells. c Metastatic PCa cells exhibit the Warburg effect with persistent TCA cycle/OXPHOS and PPP activity. Created with BioRender.com.