A new study reports that ectopic expression of fibroblast growth factor receptor 1 (FGFR1) reprogrammes energy metabolism in prostate cancer cells.

First, the effect of FGF signalling on cell metabolism was investigated. Fgfr1–/–Fgfr2–/–Frs2a–/– mouse embryonic fibroblasts (MEFΔF cells) had lower l-lactate dehydrogenase A chain (LDHA) and higher LDHB expression than parental MEFs, suggesting that FGF signalling regulates the reversible conversion of pyruvate to lactate via LDH isozymes. Indeed, further experiments revealed a shift from aerobic glycolysis to oxidative phosphorylation in MEFΔF cells and that FGFR1 enhances LDHA stability (via phosphorylation) and suppresses Ldhb transcription (via methylation).

In DU145 prostate cancer cells, FGFR1 knockout decreased LDHA protein expression and increased LDHB mRNA and protein levels, consistent with a role for FGFR1 in the post-translational and transcriptional regulation of these respective isozymes. In line with MEF observations, depletion of FGFR1 and LDHA induced a metabolic shift to oxidative phosphorylation, whereas LDHB depletion enhanced glycolysis. Subsequent DU145 xenograft experiments revealed that LDHA depletion reduced, but LDHB depletion enhanced, tumorigenicity.

Clinical relevance was assessed using a tissue microarray comprising 225 prostate cancer samples and 27 benign prostate tissue samples annotated with 15-year follow-up data. Compared with benign tissues, prostate cancer tissues had higher levels of total and phosphorylated LDHA, lower LDHB levels, and higher FGFR1 expression, which were each associated with significantly shorter biochemical-recurrence-free survival.

The study shows that FGFR1 enhances aerobic glycolysis — the Warburg effect — to drive prostate cancer progression by differentially regulating LDHA and LDHB, which could be novel prognostic biomarkers.