Metabolic Vulnerabilities of Prostate Cancer: Diagnostic and Therapeutic Opportunities

Abstract

Cancer cells hijack metabolic pathways to support bioenergetics and biosynthetic requirements for their uncontrolled growth. Thus, cancer can be considered as a metabolic disease. In this review, we discuss the main metabolic features of prostate cancer with a particular focus on the link between oncogene-directed cancer metabolic regulation, metabolism rewiring, and epigenetic regulation. The potential of using metabolic profiling as a means to predict disease behavior and to identify novel therapeutic targets and new diagnostic markers will be addressed as well as the current challenges in metabolomics analyses. Finally, diagnostic and prognostic metabolic imaging approaches, including positron emission tomography, mass spectrometry, nuclear magnetic resonance, and their translational applications, will be discussed. Here, we emphasize how targeting metabolic vulnerabilities in prostate cancer may pave the way for novel personalized diagnostic and therapeutic interventions.

Figure 1.

Prostate cells increased both the synthesis and utilization of fatty acids (FAs) during cellular transformation and prostate cancer progression. (A) Simplified illustration of FA synthesis and associated pathways. Sources of carbon for de novo FA synthesis derive primarily from glucose and glutamine. In harsh environments, acetate can also be used as a carbon source. Once synthesized, de novo FAs undergo elongation and saturation modifications. FAs are also provided by diet and they can be uptaken from the circulation through transporters, binding proteins, or passive transport. Diet is the only source of essential FAs. Once in the cells, FAs are incorporated in more complex structural, storage lipids, and inflammatory mediators or (B) oxidized in peroxisomes or mitochondria to produce energy. GLUT, glucose transporter; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; FATPs, fatty-acid transport proteins; FABP, fatty-acid-binding protein; ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; ACSS2, cytoplasmic acetyl-CoA synthetase; SCD, stearoyl-CoA desaturase; ELOVL, fatty acid elongase; α-KG, α-ketoglutarate; G3P, glyceraldehyde-3-phosphate; G6P, glucose-6-phosphate; TCA, tricarboxylic acid; MCT, monocarboxylate transporter; CPT1, carnitine palmitoyltransferase I; CPT2, carnitine palmitoyltransferase II; NADH, reduced nicotinamide adenine dinucleotide; FADH₂, reduced flavin adenine dinucleotide; ETC, electron transport chain; ATP, adenosine triphosphate.

Figure 2.

Scheme of one-carbon metabolism. Increased sarcosine levels are found in metastastic prostate cancers (PCas). THF, Tetrahydrofolate; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; GNMT, glycine N-methyltransferase; SARDH, sarcosine dehydrogenase.

Figure 3.

Oncogenes regulate tumor metabolism. This simplified scheme shows that oncogenes c-MYC and AKT mediate the regulation of metabolic enzymes/transporters. HK2, Hexokinase 2; PFKP, phosphofructokinase; PKM2, pyruvate kinase; LDHA, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; SREBPs, sterol regulatory element-binding proteins; PGD, phosphogluconate dehydrogenase; RPIA, ribose 5-phosphate isomerase A; GLS, glutaminase.

Figure 4.

Representative image of ¹¹C-acetate positron emission tomography (PET)/computerized tomography (CT). ¹¹C-acetate PET/CT was performed in a patient with increasing prostate-specific antigen (PSA) levels (biochemical recurrence) after prostatectomy. (A) Sagittal midline CT image, (B) ¹¹C-acetate image from same location as in A, and (C) fused image. Increased ¹¹C-acetate uptake (depicted with black arrows) indicates sites of otherwise inapparent metastases. (This image was kindly provided by Prof. Umar Mahmood and Dr. Pedram Heidari, Massachusetts General Hospital, Boston, MA.)