FGFR1 governs iron metabolism via regulating post-translational modification of IRP2 in prostate cancer cells

Abstract

Abstract Background The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. However, how FGFR1 facilitates PCa progression is not fully revealed, although it is known to confer tumor growth advantage and metastasis. Here we report that FGFR1 deletion in DU145 human PCa cells retards the iron metabolism and reduces transferrin receptor 1 (TFR1), which synergistically enhances the anti-cancer effect of iron chelator. Methods Prostate/PCa tissues from various ages of wildtype and TRAMP mice were collected to investigate FGFR1 expression and iron content for association with prostate cancer development and progression. FGFR1 null DU145 cells (DU145ΔR1 cells) were generated to analyze the association of FGFR1 expression with iron metabolism in PCa using iron assay kit, Western blot and qRT-PCR. Meanwhile, DFO, an iron-chelating agent, treated PCa cells to determine whether ablation of FGFR1 sensitized the cells to iron deficiency. Next, we assessed the association of TFR1 expression with Gleason scores in PCa patients through searching from the TCGA database, and investigated the relationship of FGFR1 with TFR1 expression under IRP2 regulation. Results FGFR1 and TFR1 are highly expressed in PCa, and FGFR1 overexpression increased TFR1 in PCa cell lines. Furthermore, we first time demonstrate that FGFR1 deletion boosts and shifts the degradation of iron regulatory proteins 2 (IRP2) to downregulate TFR1. Detailed characterization revealed that based on FGFR1 deletion the stability of IRP2 is broken, whose degradation is accelerated, which can be not observed without FGFR1 deletion. In addition, IRP2 overexpression rescue the malignancy degree of DU145 cells. Conclusion Our results here unravel a novel mechanism by which FGFR1 promotes PCa progression by upregulating iron metabolism, and that the FGFR1/IRP2/TFR1 axis can be a potential target for managing PCa progression.