A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for Monocarboxylate Transporters as metabolic targets for therapy

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.NPG and SSS received fellowships from the Portuguese Foundation for Science and Technology (FCT; Grant Nos SFRH/BD/61027/2009 and PTDC/SAU-MET/113415/2009, respectively). SF received a fellowship from the Sao Paulo Research Foundation (FAPESP; Grant Nos 2013/08830-2 and 2013/06802-1). We are grateful to the core facilities at the Cancer Research UK Cambridge Institute, led by James Hadfield (Genomics), Matt Eldridge (Bioinformatics) and Allen Hazelhurst (BRU). We are also grateful for support and critical advice on the project given by Christian Frezza and Marco Sciacovelli from the MRC Cancer Cell Unit, and Professor Rui Henrique from the Portuguese Institute of Oncology for providing samples from patients with metastatic prostate cancer