Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer

Abstract

Abstract The acquisition of ectopic fibroblast growthfactor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer 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 prostate cancer cells by regulating the 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 prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression. Significance: FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg. Cancer Res; 78(16); 4459–70. ©2018 AACR.