Peroxisomal Alterations in Prostate Cancer: Metabolic Shifts and Clinical Relevance

Abstract

Cancer is hallmarked by uncontrolled cell proliferation and enhanced cell survival, driven by a complex interplay of factors-including genetic and epigenetic changes-that disrupt metabolic and signaling pathways and impair organelle function. While the roles of mitochondria and the endoplasmic reticulum in cancer are widely recognized, emerging research is now drawing attention to the involvement of peroxisomes in tumor biology. Peroxisomes are essential for lipid metabolism, including fatty acid α- and β-oxidation, the synthesis of docosahexaenoic acid, bile acids, and ether lipids, as well as maintaining redox balance. Despite their critical functions, the role of peroxisomes in oncogenesis remains inadequately explored. Prostate cancer (PCa), the second most common cancer in men worldwide, exhibits a unique metabolic profile compared to other solid tumors. In contrast to the glycolysis-driven Warburg effect, primary PCa relies primarily on lipogenesis and oxidative phosphorylation. Peroxisomes are intricately involved in the metabolic adaptations of PCa, influencing both disease progression and therapy resistance. Key alterations in peroxisomal activity in PCa include the increased oxidation of branched-chain fatty acids, upregulation of α-methylacyl coenzyme A racemase (a prominent PCa biomarker), and downregulation of 1-alkyl-glycerone-3-phosphate synthase and catalase. This review critically examines the role of peroxisomes in PCa metabolism, progression, and therapeutic response, exploring their potential as biomarkers and targets for therapy. We also consider their relationship with androgen receptor signaling. A deeper understanding of peroxisome biology in PCa could pave the way for new therapies to improve patient outcomes.

Keywords: androgen receptor; ether lipids; fatty acid oxidation; metabolic rewiring; peroxisomes; prostate cancer; redox homeostasis.

Figure 1

Differential expression of peroxisome-related genes in primary prostate adenocarcinoma compared to normal tissue. Volcano plots display differential gene expression between primary prostate adenocarcinoma (n = 497) and normal prostate tissue (n = 52): genes encoding proteins involved in (A) peroxisome homeostasis, (B) peroxisomal lipid metabolism, and (C) peroxisomal redox metabolism. Only genes with statistically significant changes in expression (adjusted p-value < 0.05; −Log₁₀ adjusted p-value > 1.3; indicated by a dotted horizontal line) are labeled. Data were obtained from The Cancer Genome Atlas Program (TCGA) mRNA expression profiles of primary prostate cancer and normal tissue, accessed via the University of Alabama at Birmingham Cancer Data Analysis portal (UALCAN; https://ualcan.path.uab.edu/; accessed on 12 March 2025).

Figure 2

Peroxisomal involvement in ether lipid synthesis. The pathway initiates in peroxisomes, where glycerone-3-phosphate O-acyltransferase (GNPAT) catalyzes the formation of 1-acyl-dihydroxyacetone-3-phosphate (1-acyl-DHAP) from DHAP and acyl-CoA. 1-alkyl-glycerone-3-phosphate synthase (AGPS) then replaces the acyl moiety with a fatty alcohol, produced by fatty acyl-CoA reductase (FAR), to form the ether bond in 1-O-alkyl-DHAP. This intermediate is subsequently transferred to the ER for further processing into ether lipids. Although peroxisomal membrane protein 4 (PXMP4) is predicted to act upstream of, or within, the ether lipid metabolic process, its exact function remains unclear. Structural differences at the sn-1 position between plasmanyl and plasmenyl ether lipids are highlighted. Downregulation in PCa is represented by a red arrow pointing downward.

Figure 3

Schematic representation of the peroxisomal β-oxidation machinery. The diagram depicts the key transporters, enzymes, and metabolic steps involved in the peroxisomal β-oxidation pathway. Upregulation and downregulation in PCa are represented by red upward and downward arrows, respectively. Notable components include ATP binding cassette subfamily D (ABCD), peroxisomal 3-ketoacyl-CoA thiolase (ACAA1), acyl-CoA oxidase (ACOX), acyl-CoA thioesterase (ACOT), calcium/calmodulin-dependent kinase II (CaMKII), carnitine acetyltransferase (CRAT), carnitine octanoyltransferase (CROT), hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4), enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), and sterol carrier protein x (SCPx).

Figure 4

Auxiliary enzymes involved in peroxisomal β-oxidation. This schematic illustrates the chemical reactions catalyzed by (A) α-methylacyl coenzyme A racemase (AMACR), (B) 2,4-dienoyl CoA reductase 2 (DECR2), (C) 2-enoyl-CoA isomerase (ECI2), and (D) Δ^3,5,Δ^2,4-enoyl-CoA isomerase (ECH1) in the peroxisomal β-oxidation pathway. AMACR is essential for the β-oxidation of 2-methyl-branched-chain fatty acids, whereas DECR2, ECI2, and ECH1 participate in the β-oxidation of unsaturated fatty acids. Red upward arrows represent upregulation.

Figure 5

Schematic overview of the enzymatic steps involved in the peroxisomal α-oxidation of phytanic acid. Key enzymes include ATP-binding cassette subfamily D member 3 (ABCD3), α-methylacyl coenzyme A racemase (AMACR), 2-hydroxyacyl-CoA lyase 1 (HACL1), peroxisomal trans-2-enoyl-CoA reductase (PECR), and phytanoyl-CoA 2-hydroxylase (PHYH). Upregulation and downregulation in PCa are indicated by red upward and downward arrows, respectively.