Autocrine Fibroblast Growth Factor Receptor 1 Signaling Activates Lactate Dehydrogenase A-Aerobic Glycolysis for Advanced Human Prostate Tumor Growth.

Abstract

Background: Fibroblast growth factor receptor 1 (FGFR1) signaling is activated by fibroblast growth factors (FGFs) during prostate cancer (PCa) progression. However, the mechanisms by which FGFR1 signaling regulates PCa progression are not fully understood. The objective of this study was to investigate the cross talk between autocrine FGF/FGFR1 loop and aerobic glycolysis in progression of advanced PCa. Method: DU145 cells were used as an advanced PCa model. FGFR1 expression was knockdowned by stable expression of anti-FGFR1 shRNA, and lactate dehydrogenase A (LDHA) levels were rescued by ectopic expression of LDHA cDNA. Protein expression was determined using Western blotting and immunohistochemistry. Tumorigenicity of DU145 cells was defined by cell growth, invasion, and survival in both cultures and xenografts in mice. Results: Here, we showed that DU145 cells in cultures expressed both FGF2 and FGFR1, and knockdown of FGFR1 expression or inactivation of FGFR1 signaling reduced LDHA expression or aerobic glycolysis, which was correlated with suppression of both cell proliferation and invasion, and with promotion of apoptosis. Ectopic expression of LDHA cDNA rescued LDHA levels in FGFR1-deficient cells, restoring their aerobic glycolysis, cell growth, and survival. Similarly, the growth rates of xenografted DU145 cells in mice were decreased by the loss of FGFR1 expression but were rescued by the ectopic expression of LDHA. Conclusion: Our data indicate autocrine FGF/FGFR1 signaling regulates aerobic glycolysis in PCa DU145 cells via LDHA, suggesting the potential of targeting FGFs/FGFRs-LDHA for the management of advanced PCa. The regulation of aerobic glycolysis by other growth factors in PCa remains further investigation.