Emerging Hallmarks of Metabolic Reprogramming in Prostate Cancer

Abstract

Prostate cancer (PCa) is the most common male malignancy and the fifth leading cause of cancer death in men worldwide. Prostate cancer cells are characterized by a hybrid glycolytic/oxidative phosphorylation phenotype determined by androgen receptor signaling. An increased lipogenesis and cholesterogenesis have been described in PCa cells. Many studies have shown that enzymes involved in these pathways are overexpressed in PCa. Glutamine becomes an essential amino acid for PCa cells, and its metabolism is thought to become an attractive therapeutic target. A crosstalk between cancer and stromal cells occurs in the tumor microenvironment because of the release of different cytokines and growth factors and due to changes in the extracellular matrix. A deeper insight into the metabolic changes may be obtained by a multi-omic approach integrating genomics, transcriptomics, metabolomics, lipidomics, and radiomics data.

Keywords: androgen receptor; biomarkers; castration resistance; metabolomics; metastasis; prostate cancer.

Figure 1

Oncoprints of fatty acid (FA) metabolism genes in the cancer genome atlas (TCGA, PanCancer Atlas) PCa patient cohort (PRAD). About 88% of the tumors from 489 patients in PRAD showed altered gene copy number or expression of FA metabolism-related genes. ACLY: ATP citrate lyase; ACACA: acetyl-CoA carboxylase alpha (ACC); FASN: fatty acid synthase; ACCS2: acyl-CoA synthetase short-chain family member 2; MLYCD: malonyl-CoA decarboxylase; SCD: stearoyl-CoA desaturase; SREBF1: sterol regulatory element-binding transcription factor 1 (SPREBP1); CPT1A: carnitine palmitoyltransferase 1A; PPARA: peroxisome proliferator-activated receptor alpha; GPAM: glycerol-3-phosphate acyltransferase; AGPAT: 1-acylglycerol-3-phosphate O-acyltransferase; LPCAT1: lysophosphatidylcholine acyltransferase 1; LPIN1: lipin 1; DGAT1: diacylglycerol O-acyltransferase 1; PNPLA2: patatin-like phospholipase domain containing 2; LIPE: lipase, hormone-sensitive; MGLL: monoglyceride lipase.

Figure 2

Overview of prostate cancer cell metabolism and its crosstalk with stromal components. TAF: tumor-associated fibroblast; MCT4: monocarboxylate transporter 4; MCT1: monocarboxylate transporter 1; GLUT: glucose transporter; G6P: glucose 6-phosphate; PPP: pentose phosphate pathway; α-KG: α-ketoglutarate; OAA: oxaloacetate; Ac-CoA: acyl-CoA; ASCT2 (SLC1A5): neutral amino acid transporter; ATP: adenosine triphosphate.