Metabolic reprogramming in prostate cancer

Abstract

Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic prostate cancer remains incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures and metabolic reprogramming, all of which enable the tumour to serially adapt to drugs during the course of treatment. In this review, we focus on alterations in the metabolism of prostate cancer, including genetic signatures and molecular pathways associated with metabolic reprogramming. Advances in our understanding of prostate cancer metabolism might help to explain many of the adaptive responses that are induced by therapy, which might, in turn, lead to the attainment of more durable therapeutic responses.

Fig. 1. Core metabolic pathways.

Catabolic pathways—for example glycolysis, oxidative phosphorylation via tricarboxylic acid cycle (TCA) and lipogenesis—involve the breakdown of major nutrients (glucose, amino acids and fatty acids) to generate energy, which is either stored for later use or released as heat. Anabolic pathways then build macromolecules out of the products of catabolism, which are building blocks for cell structures and help to maintain the cell. Cells also produce lactate, ammonia, carbon dioxide and reactive oxygen species (ROS) as by-products of the metabolic breakdown of sugars, fats and proteins. Emerging studies have revealed a functional role for many of these metabolic by-products. For many years, lactate was seen as the metabolic waste product of glycolytic metabolism; however, new roles for lactate in the tumour microenvironment as a metabolic fuel, modulator of extracellular pH or as a signalling molecule have emerged. Ammonia, generated as a by-product of proteins that are broken into amino acids by amino acid lyases and nucleotide deaminases, is toxic at high concentrations and, thus, gets further converted into urea. ROS, mainly generated through NADPH oxidase (NOX4) and through electron leak from electron transport chain (ETC) complexes, are potent mitogens that promote proliferation, differentiation and migration.

Fig. 2. Metabolic pathways adopted by cancer cells under varying nutrient conditions.

The proximity to the vasculature determines the accessibility of cells within solid tumours to nutrients. Cells that are near to the vasculature acquire nutrients and oxygen to fuel anabolic pathways, but cells that are further away have decreased accessibility to nutrients and oxygen and might employ alternative pathways, including oxidation of fatty acids, to meet the bioenergetic demands of proliferation and growth.

Fig. 3. Metabolism of normal versus transformed prostate epithelial cells.

Normal prostate epithelial cells assimilate glucose and aspartate to synthesise and secrete citrate. Androgen-receptor (AR)-mediated metabolic reprogramming drives enhanced oxidative phosphorylation and lipogenesis inside the transformed prostate epithelium. Normal prostate epithelial cells produce most of their ATP via glycolysis, whereas oxidative phosphorylation remains the main source of ATP generation in early prostate adenocarcinoma. Highlighted red and green arrows represent metabolic pathways that are important in normal and transformed prostate epithelial cells. Solid arrows represent single metabolic steps and dashed arrows represent simplified multistep processes. SCL39A1, SLC25A1, SLC1A1, GLUTs and MCTs represent zinc, citrate, aspartate, glucose, pyruvate and lactate transporters, respectively.

Fig. 4. Mechanism of action of exercise in prostate cancer related metabolic syndrome.

Potential mechanisms of improvement due to exercise in androgen deprivation therapy (ADT) associated metabolic syndrome. Dashed arrow denotes the inhibitory effect of exercise on prostate cancer progression. Upward arrows denote increased activity whereas downward arrows represent compromised level.