title: A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy.
abstract: Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia-inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors.
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Nelma
authors: N
authors: Pertega-Gomes
authors: Department of Morphology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, Brazil.
authors: Sergio
authors: S
authors: Felisbino
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Charlie E
authors: CE
authors: Massie
authors: Department of Pathology, Centro Hospitalar do Porto, Portugal.
authors: Jose R
authors: JR
authors: Vizcaino
authors: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal.
authors: Ricardo
authors: R
authors: Coelho
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Chiranjeevi
authors: C
authors: Sandi
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences,University of Minho, Braga, Portugal.|ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimaraes, Portugal.
authors: Susana
authors: S
authors: Simoes-Sousa
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Sarah
authors: S
authors: Jurmeister
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Antonio
authors: A
authors: Ramos-Montoya
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Mohammad
authors: M
authors: Asim
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Maxine
authors: M
authors: Tran
authors: Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Portugal.
authors: Elsa
authors: E
authors: Oliveira
authors: Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Portugal.
authors: Alexandre
authors: A
authors: Lobo da Cunha
authors: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal.|Department of Pathology and Oncology, Medical Faculty of the University of Porto, Portugal.
authors: Valdemar
authors: V
authors: Maximo
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences,University of Minho, Braga, Portugal.|ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimaraes, Portugal.
authors: Fatima
authors: F
authors: Baltazar
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.|Department of Urology, University of Cambridge, and S4, Department of Oncology, Addenbrooke's Hospital, Cambridge, UK.
authors: David E
authors: DE
authors: Neal
authors: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.
authors: Lee G D
authors: LG
authors: Fryer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D027501:Monocarboxylic Acid Transporters; D019344:Lactic Acid
keywords: cell metabolism; metabolic targets; monocarboxylate transporters; poor prognosis markers; prostate cancer