bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021‒07‒18
nineteen papers selected by
Sreeparna Banerjee
Middle East Technical University

  1. EMBO Rep. 2021 Jul 14. e51981
      Glutaminolysis is known to correlate with ovarian cancer aggressiveness and invasion. However, how this affects the tumor microenvironment is elusive. Here, we show that ovarian cancer cells become addicted to extracellular glutamine when silenced for glutamine synthetase (GS), similar to naturally occurring GS-low, glutaminolysis-high ovarian cancer cells. Glutamine addiction elicits a crosstalk mechanism whereby cancer cells release N-acetylaspartate (NAA) which, through the inhibition of the NMDA receptor, and synergistically with IL-10, enforces GS expression in macrophages. In turn, GS-high macrophages acquire M2-like, tumorigenic features. Supporting this in␣vitro model, in silico data and the analysis of ascitic fluid isolated from ovarian cancer patients prove that an M2-like macrophage phenotype, IL-10 release, and NAA levels positively correlate with disease stage. Our study uncovers the unprecedented role of glutamine metabolism in modulating macrophage polarization in highly invasive ovarian cancer and highlights the anti-inflammatory, protumoral function of NAA.
    Keywords:  IL-10; N-acetylaspartate; TAMs; metabolism; ovarian cancer
  2. FEBS J. 2021 Jul 16.
      Autophagy is a catabolic process that captures cellular waste and degrades them in the lysosome. The main function of autophagy is quality control of cytosolic proteins and organelles, and intracellular recycling of nutrients in order to maintain cellular homeostasis. Autophagy is upregulated in many cancers to promote cell survival, proliferation and metastasis. Both cell-autonomous autophagy (also known as tumor autophagy) and non-cell autonomous autophagy (also known as host autophagy) supports tumorigenesis through different mechanisms, including inhibition of p53 activation, sustaining redox homeostasis, maintenance of essential amino acids levels in order to support energy production and biosynthesis, and inhibition of anti-tumor immune responses. Therefore, autophagy may serve as a tumor-specific vulnerability and targeting autophagy could be a novel strategy in cancer treatment.
    Keywords:  Autophagy; Cancer; Cancer Metabolism; Immune Response; Metastasis; p53
  3. Gastroenterology. 2021 Jul 07. pii: S0016-5085(21)03159-0. [Epub ahead of print]
      BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown.METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was utilized for therapeutic studies in organoids and patient-derived xenografts.
    RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in PDAC patients. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited anti-tumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine.
    CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased non-canonical utilization of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
    Keywords:  GOT1; Glutamine Metabolism; Glutathione Metabolism; Pancreatic Cancer; SIRT5
  4. J Biol Chem. 2021 Jul 13. pii: S0021-9258(21)00754-7. [Epub ahead of print] 100954
      PPARδ is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase AMPK is a critical regulator of cellular energy in coordination with PPARδ. However, the molecular mechanism of AMPK/PPARδ pathway on cancer progression is still unclear. Here we found that activated AMPK induced PPARδ-S50 phosphorylation in cancer cells, while the PPARδ/S50A (non-phosphorylation mimic) mutant reversed this event. Further analysis showed that the PPARδ/S50E (phosphorylation mimic) but not the PPARδ/S50A mutant increased PPARδ protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPARδ. Furthermore, PPARδ-S50 phosphorylation decreased PPARδ transcription activity and alleviated PPARδ-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPARδ/S50E mutant but not the PPARδ/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPARδ-S50 phosphorylation, accumulation of misfolded PPARδ protein, and inhibition of PPARδ transcription activity contributing to the suppression of colon tumor formation.
    Keywords:  AMPK; PPARδ; cancer; misfolded protein; phosphorylation
  5. Nat Rev Cancer. 2021 Jul 16.
      Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Cancer cells autonomously alter their flux through various metabolic pathways in order to meet the increased bioenergetic and biosynthetic demand as well as mitigate oxidative stress required for cancer cell proliferation and survival. Cancer driver mutations coupled with environmental nutrient availability control flux through these metabolic pathways. Metabolites, when aberrantly accumulated, can also promote tumorigenesis. The development and application of new technologies over the last few decades has not only revealed the heterogeneity and plasticity of tumours but also allowed us to uncover new metabolic pathways involved in supporting tumour growth. The tumour microenvironment (TME), which can be depleted of certain nutrients, forces cancer cells to adapt by inducing nutrient scavenging mechanisms to sustain cancer cell proliferation. There is growing appreciation that the metabolism of cell types other than cancer cells within the TME, including endothelial cells, fibroblasts and immune cells, can modulate tumour progression. Because metastases are a major cause of death of patients with cancer, efforts are underway to understand how metabolism is harnessed by metastatic cells. Additionally, there is a new interest in exploiting cancer genetic analysis for patient stratification and/or dietary interventions in combination with therapies that target metabolism. In this Perspective, we highlight these main themes that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing questions that remain unanswered.
  6. EMBO J. 2021 Jul 16. e107480
      The mTORC1 pathway plays key roles in regulating various biological processes, including sensing amino acid deprivation and driving expression of ribosomal protein (RP)-coding genes. In this study, we observed that depletion of glutamate dehydrogenase 1 (GDH1), an enzyme that converts glutamate to α-ketoglutarate (αKG), confers resistance to amino acid deprivation on kidney renal clear cell carcinoma (KIRC) cells. Mechanistically, under conditions of adequate nutrition, GDH1 maintains RP gene expression in a manner dependent on its enzymatic activity. Following amino acid deprivation or mTORC1 inhibition, GDH1 translocates from mitochondria to the cytoplasm, where it becomes ubiquitinated and degraded via the E3 ligase RNF213. GDH1 degradation reduces intracellular αKG levels by more than half and decreases the activity of αKG-dependent lysine demethylases (KDMs). Reduced KDM activity in turn leads to increased histone H3 lysine 9 and 27 methylation, further suppressing RP gene expression and preserving nutrition to support cell survival. In summary, our study exemplifies an economical and efficient strategy of solid tumor cells for coping with amino acid deficiency, which might in the future be targeted to block renal carcinoma progression.
    Keywords:  GDH1; amino acid deprivation; kidney cancer; ribosomes; αKG
  7. Acta Pharmacol Sin. 2021 Jul 15.
      Bergenin is a natural PPARγ agonist that can prevent neutrophil aggregation, and often be used in clinics for treating respiratory diseases. Recent data show that Th17 cells are important for neutrophil aggregation and asthma through secreting IL-17A. In this study, we investigated the effects of bergenin on Th17 differentiation in vitro and subsequent neutrophilic asthma in mice. Naïve T cells isolated from mouse mesenteric lymph nodes were treated with IL-23, TGF-β, and IL-6 to induce Th17 differentiation. We showed that in naïve T cells under Th17-polarizing condition, the addition of bergenin (3, 10, 30 μM) concentration-dependently decreased the percentage of CD4+ IL-17A+ T cells and mRNA expression of specific transcription factor RORγt, and function-related factors IL-17A/F, IL-21, and IL-22, but did not affect the cell vitality and apoptosis. Furthermore, bergenin treatment prevented GLS1-dependent glutaminolysis in the progress of Th17 differentiation, slightly affected the levels of SLC1A5, SLC38A1, GLUD1, GOT1, and GPT2. Glutamine deprivation, the addition of glutamate (1 mM), α-ketoglutarate (1 mM), or GLS1 plasmid all significantly attenuated the above-mentioned actions of bergenin. Besides, we demonstrated that bergenin (3, 10, and 30 μM) concentration-dependently activated PPARγ in naïve T cells, whereas PPARγ antagonist GW9662 and siPPARγ abolished bergenin-caused inhibition on glutaminolysis and Th17 differentiation. Furthermore, we revealed that bergenin inhibited glutaminolysis by regulating the level of CDK1, phosphorylation and degradation of Cdh1, and APC/C-Cdh1-mediated ubiquitin-proteasomal degradation of GLS1 after activating PPARγ. We demonstrated a correlation existing among bergenin-affected GLS1-dependent glutaminolysis, PPARγ, "CDK1-APC/C-Cdh1" signaling, and Th17 differentiation. Finally, the therapeutic effect and mechanisms for bergenin-inhibited Th17 responses and neutrophilic asthma were confirmed in a mouse model of neutrophilic asthma by administration of GW9662 or GLS1 overexpression plasmid in vivo. In conclusion, bergenin repressed Th17 differentiation and then alleviated neutrophilic asthma in mice by inhibiting GLS1-dependent glutaminolysis via regulating the "CDK1-APC/C-Cdh1" signaling after activating PPARγ.
    Keywords:  GLS1; Th17 differentiation; bergenin; glutaminolysis; immunity-related diseases; neutrophilic asthma
  8. J Biol Chem. 2021 Jul 09. pii: S0021-9258(21)00750-X. [Epub ahead of print] 100950
      Mammalian cells synthesize H2S from sulfur containing amino acids and are also exposed to exogenous sources of this signaling molecule, notably from gut microbes. As an inhibitor of complex IV in the electron transport chain, H2S can have a profound impact on metabolism, suggesting the hypothesis that metabolic reprogramming is a primary mechanism by which H2S signals. In this study, we report that H2S increases lipogenesis in many cell types, using carbon derived from glutamine rather than from glucose. H2S-stimulated lipid synthesis is sensitive to the mitochondrial NAD(P)H pools and is enabled by reductive carboxylation of α-ketoglutarate. Lipidomics analysis revealed that H2S elicits time-dependent changes across several lipid classes, e.g., upregulating triglycerides while down regulating phosphatidylcholine. Direct analysis of triglyceride concentration revealed that H2S induces a net increase in the size of this lipid pool. These results provide a mechanistic framework for understanding the effects of H2S on increasing lipid droplets in adipocytes and population studies that have pointed to a positive correlation between cysteine (a substrate for H2S synthesis) and fat mass.
  9. Adv Exp Med Biol. 2021 ;1332 129-149
      Amino acids are integral for human health, influencing an array of physiological processes from gene expression to vasodilation to the immune response. In accordance with this expansive range of unique functions, the tissues of the body engage in a complex interplay of amino acid exchange and metabolism to respond to the organism's dynamic needs for a range of nitrogenous products. Interorgan amino acid metabolism is required for numerous metabolic pathways, including the synthesis of functional amino acids like arginine, glutamate, glutamine, and glycine. This physiological process requires the cooperative handling of amino acids by organs (e.g., the small intestine, skeletal muscle, kidneys, and liver), as well as the complete catabolism of nutritionally essential amino acids such as the BCAAs, with their α-ketoacids shuttled from muscle to liver. These exchanges are made possible by several mechanisms, including organ location, as well as the functional zonation of enzymes and the cell-specific expression of amino acid transporters. The cooperative handling of amino acids between the various organs does not appear to be under the control of any centralized regulation, but is instead influenced by factors such as fluctuations in nutrient availability, hormones, changes associated with development, and altered environmental factors. While the normal function of these pathways is associated with health and homeostasis, affected by physical activity, diet and body composition, dysregulation is observed in numerous disease states, including cardiovascular disease and cancer cachexia, presenting potential avenues for the manipulation of amino acid consumption as part of the therapeutic approach to these conditions in individuals.
    Keywords:  Amino acids; Diets; Diseases; Exercise; Health; Humans; Supplementation
  10. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab057
      Background: Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzyme activity is crucial for the generation of reducing potential in normal cells, yet the impact of the mutation on the cellular antioxidant system in glioma is not understood. The aim of this study was to determine how glutathione (GSH), the main antioxidant in the brain, is maintained in IDH1-mutant gliomas, despite an altered NADPH/NADP balance.Methods: Proteomics, metabolomics, metabolic tracer studies, genetic silencing, and drug targeting approaches in vitro and in vivo were applied. Analyses were done in clinical specimen of different glioma subtypes, in glioma patient-derived cell lines carrying the endogenous IDH1 mutation and corresponding orthotopic xenografts in mice.
    Results: We find that cystathionine-γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis, is specifically upregulated in IDH1-mutant astrocytomas. CSE inhibition sensitized these cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with an increase in reactive oxygen species and reduced GSH synthesis. Propargylglycine (PAG), a brain-penetrant drug specifically targeting CSE, led to delayed tumor growth in mice.
    Conclusions: We show that IDH1-mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis via CSE to maintain the antioxidant defense, which highlights a novel metabolic vulnerability that may be therapeutically exploited.
    Keywords:  IDH mutation; antioxidant defense; cysteine; glioma; glutathione; transsulfuration pathway
  11. Adv Exp Med Biol. 2021 ;1332 17-33
      Amino acids are the main building blocks for life. Aside from their roles in composing proteins, functional amino acids and their metabolites play regulatory roles in key metabolic cascades, gene expressions, and cell-to-cell communication via a variety of cell signaling pathways. These metabolic networks are necessary for maintenance, growth, reproduction, and immunity in humans and animals. These amino acids include, but are not limited to, arginine, glutamine, glutamate, glycine, leucine, proline, and tryptophan. We will discuss these functional amino acids in cell signaling pathways in mammals with a particular emphasis on mTORC1, AMPK, and MAPK pathways for protein synthesis, nutrient sensing, and anti-inflammatory responses, as well as cell survival, growth, and development.
    Keywords:  AMPK; Functional amino acids; MAPK; Sensor; Transceptor; mTORC1
  12. Front Mol Biosci. 2021 ;8 691795
      Cisplatin is a chemotherapy drug commonly used in cancer treatment. Tumour cells are more sensitive to cisplatin than normal cells. Cisplatin exerts an antitumour effect by interfering with DNA replication and transcription processes. However, the drug-resistance properties of tumour cells often cause loss of cisplatin efficacy and failure of chemotherapy, leading to tumour progression. Owing to the large amounts of energy and compounds required by tumour cells, metabolic reprogramming plays an important part in the occurrence and development of tumours. The interplay between DNA damage repair and metabolism also has an effect on cisplatin resistance; the molecular changes to glucose metabolism, amino acid metabolism, lipid metabolism, and other metabolic pathways affect the cisplatin resistance of tumour cells. Here, we review the mechanism of action of cisplatin, the mechanism of resistance to cisplatin, the role of metabolic remodelling in tumorigenesis and development, and the effects of common metabolic pathways on cisplatin resistance.
    Keywords:  DNA damage repair; ROS; cisplatin; resistance; tumour metabolism
  13. Cell Oncol (Dordr). 2021 Jul 09.
      BACKGROUND: The ability of cancer cells to develop treatment resistance is one of the primary factors that prevent successful treatment. Although initially thought to be dysfunctional in cancer, mitochondria are significant players that mediate treatment resistance. Literature indicates that cancer cells reutilize their mitochondria to facilitate cancer progression and treatment resistance. However, the mechanisms by which the mitochondria promote treatment resistance have not yet been fully elucidated.CONCLUSIONS AND PERSPECTIVES: Here, we describe various means by which mitochondria can promote treatment resistance. For example, mutations in tricarboxylic acid (TCA) cycle enzymes, i.e., fumarate hydratase and isocitrate dehydrogenase, result in the accumulation of the oncometabolites fumarate and 2-hydroxyglutarate, respectively. These oncometabolites may promote treatment resistance by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, inhibiting the anti-tumor immune response, or promoting angiogenesis. Furthermore, stromal cells can donate intact mitochondria to cancer cells after therapy to restore mitochondrial functionality and facilitate treatment resistance. Targeting mitochondria is, therefore, a feasible strategy that may dampen treatment resistance. Analysis of tumoral DNA may also be used to guide treatment choices. It will indicate whether enzymatic mutations are present in the TCA cycle and, if so, whether the mutations or their downstream signaling pathways can be targeted. This may improve treatment outcomes by inhibiting treatment resistance or promoting the effectiveness of anti-angiogenic agents or immunotherapy.
    Keywords:  2-Hydroxyglutarate; Fumarate; Mitochondria; Mitochondrial transfer; Treatment resistance
  14. Free Radic Biol Med. 2021 Jul 13. pii: S0891-5849(21)00418-4. [Epub ahead of print]
      Reactive oxygen species (ROS)/reactive nitrogen species (RNS)-mediated ferroptosis becomes a novel effective target for anti-cancer treatment. In the present study, we tested the hypothesis that 18-β-glycyrrhetinic acid (GA), an active compound from medicinal herbal Licorice, could induce the production of ROS/RNS, increase lipid peroxidation and trigger ferroptosis in MDA-MB-231 triple negative breast cancer cells. To confirm the GA's anti-cancer effects, we detected cell viability, apoptosis and ferroptosis in the MDA-MB-231 cells. To explore the effects of GA on inducing ferroptosis, we measured ROS/RNS production, lipid peroxidation, ferrous ion, glutathione (GSH), System Xc-, GPX4, glutathione peroxidases (GPX), NADPH oxidase and iNOS in the MDA-MB-231 cells. The major discoveries are included as below: (1) GA treatment selectively decreased cell viability and induced ferroptosis companied with the increased lipid peroxidation and ferrous ion in the MDA-MB-231 triple negative breast cancer cells. Iron chelator deferoxamine mesylate (DFO) and ferroptosis inhibitor Ferrostatin-1 abolished the effects of GA. (2) GA treatment up-regulated the expression and activity of NADPH oxidase and iNOS, and increased ROS/RNS productions (O2•-, •OH, NO and ONOO-) in the MDA-MB-231 cells; (3) GA down-regulated the expression of SLC7A11 of System Xc-, decreased glutathione (GSH) level and inhibited GPX activity. Taken together, GA could promote the productions of ROS and RNS via activating NADPH oxidases and iNOS, and decreasing GSH and GPX activity, subsequently aggravating lipid peroxidation and triggering ferroptosis in triple-negative breast cancer cells.
    Keywords:  Breast cancer; Ferroptosis; Glycyrrhetinic acid; NADPH oxidase; RNS; ROS; iNOS
  15. Nat Rev Cancer. 2021 Jul 09.
      Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.
  16. Am J Cancer Res. 2021 ;11(6): 2911-2927
      Acute myeloid leukemia (AML) is a highly heterogenous and aggressive disease with a poor prognosis, necessitating further improvements in treatment therapies. Recently, several targeted therapies have become available for specific AML populations. To identify potential new therapeutic targets for AML, we analyzed published genome wide CRISPR-based screens to generate a gene essentiality dataset across a panel of 14 human AML cell lines while eliminating common essential genes through integration analysis with core fitness genes among 324 human cancer cell lines and DepMap databases. The key glutathione metabolic enzyme, glutamate-cysteine ligase catalytic subunit (GCLC), met the selection threshold. Using CRISPR knockout, GCLC was confirmed to be essential for the cell growth, survival, clonogenicity, and leukemogenesis in AML cells but was comparatively dispensable for normal hematopoietic stem and progenitor cells (HSPCs), indicating that GCLC is a potential therapeutic target for AML. In addition, we evaluated the essentiality of GCLC in solid tumors and demonstrated that GCLC represents a synthetic lethal target for ARID1A-deficient ovarian and gastric cancers.
    Keywords:  Acute myeloid leukemia (AML); CRISPR; glutamate-cysteine ligase catalytic subunit (GCLC); glutathione metabolic enzyme; synthetic lethality
  17. J Innate Immun. 2021 Jul 09. 1-17
      Macrophages, the central mediators of innate immune responses, being in the first-line of defense, they have to readily respond to pathogenic or tissue damage signals to initiate the inflammatory cascade. Such rapid responses require energy to support orchestrated production of pro-inflammatory mediators and activation of phagocytosis. Being a cell type that is present in diverse environments and conditions, macrophages have to adapt to different nutritional resources. Thus, macrophages have developed plasticity and are capable of utilizing energy at both normoxic and hypoxic conditions and in the presence of varying concentrations of glucose or other nutrients. Such adaptation is reflected on changes in signaling pathways that modulate responses, accounting for the different activation phenotypes observed. Macrophage metabolism has been tightly associated with distinct activation phenotypes within the range of M1-like and M2-like types. In the context of diseases, systemic changes also affect macrophage metabolism, as in diabetes and insulin resistance, which results in altered metabolism and distinct activation phenotypes in the adipose tissue or in the periphery. In the context of solid tumors, tumor-associated macrophages adapt in the hypoxic environment, which results in metabolic changes that are reflected on an activation phenotype that supports tumor growth. Coordination of environmental and pathogenic signals determines macrophage metabolism, which in turn shapes the type and magnitude of the response. Therefore, modulating macrophage metabolism provides a potential therapeutic approach for inflammatory diseases and cancer.
    Keywords:  Cancer; Diabetes; Inflammation; Insulin; Macrophage; Metabolism; Obesity
  18. Annu Rev Nutr. 2021 Jul 16.
      The reactions of the tricarboxylic acid (TCA) cycle allow the controlled combustion of fat and carbohydrate. In principle, TCA cycle intermediates are regenerated on every turn and can facilitate the oxidation of an infinite number of nutrient molecules. However, TCA cycle intermediates can be lost to cataplerotic pathways that provide precursors for biosynthesis, and they must be replaced by anaplerotic pathways that regenerate these intermediates. Together, anaplerosis and cataplerosis help regulate rates of biosynthesis by dictating precursor supply, and they play underappreciated roles in catabolism and cellular energy status. They facilitate recycling pathways and nitrogen trafficking necessary for catabolism, and they influence redox state and oxidative capacity by altering TCA cycle intermediate concentrations. These functions vary widely by tissue and play emerging roles in disease. This article reviews the roles of anaplerosis and cataplerosis in various tissues and discusses how they alter carbon transitions, and highlights their contribution to mechanisms of disease. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see for revised estimates.
  19. Br J Cancer. 2021 Jul 14.
      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.