A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy.
Bottom Line: 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.
Affiliation: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.Show MeSH
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Mentions: Since the androgen receptor (AR) is an important regulator of metabolic pathways in PCa, regulating the expression of various genes involved in metabolism , we sought to determine potential cross-regulation between MCTs and AR signalling. We found that MCT1 levels were higher in PC3 and LNCaP cells compared to DU145 and 22RV1 cell lines (Figure 5A). MCT4 protein was only present in the AR-negative cells, PC3 and DU145 (Figure 5B). In LNCaP cells treated with the synthetic androgen R1881, no major changes were observed for MCT1 and MCT4 mRNA expression levels during up to 24 h of treatment (Figure 5C, D). While MCT1 has emerged as a new anticancer target and a first MCT1 inhibitor is currently entering clinical trials [29,30], little is known about its regulation by typical parameters of the tumour microenvironment. Figure 5E–H shows the expression levels of MCTs in LNCaP and PC3 cell lines when grown under different oxygen conditions. The results clearly show an increase in MCTs expression with hypoxia, a typical feature of the tumour microenvironment. Figure 5K, L, shows a comparison of SLC16A1 and SLC16A3 peaks from ChIP-seq in LNCaP cell lines growing under different oxygen conditions. While no HIF-1α binding peaks are seen for SLC16A1 (Figure 5I), there is a clear HIF1A binding peak upstream of the SLC16A3 locus (Figure 5J). Figure 5M shows a Venn diagram demonstrating the overlap between groups of genes expressed by LNCaP cells under different conditions (M Tran, unpublished results). It is interesting to observe that SLC16A3, LDHA, PDK1 and CA9, previously associated with poor prognosis, appear in the group of genes expressed when hypoxia is present, with or without androgen stimulation.
Affiliation: Uro-oncology Research Group, Cancer Research UK (CRUK) Cambridge Institute, Cambridge, UK.