Aberrant FGFR tyrosine kinase signaling enhances the Warburg effect by reprogramming LDH isoform expression and activity in prostate cancer

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. How it contributes to PCa progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here we report that FGFR1 tyrosine kinase reprograms the energy metabolism of PCa cells by regulating expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with PCa. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of PCa cells, representing a hallmark change in PCa progression.

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