Crosstalk of FGFR1 signaling and choline metabolism promotes cell proliferation and survival in prostate cancer cells

Abstract

The acquisition of ectopic type I fibroblast growth factor receptor (FGFR1) is a common feature of prostate cancer (PCa), the most frequently diagnostic cancer in men.However, how ectopic FGFR1 contributes to PCa progression is not well understood.In our study we showed that ablation of FGFR1 in DU145 human PCa cells changed the cell metabolite profile. Among the changes, the choline metabolism profile was the most significantly altered by FGFR1 ablation. Detailed characterization revealed that ablation of FGFR1 altered expression of multiple choline metabolism enzymes.Among the changes of FGFR1-regulated choline metabolic enzymes, downregulation of choline kinase α (CHKA) is the most prominent changes, which phosphorylates free choline to phosphocholine. Ablation of FGFR1 blunted the activity of choline to promote cell proliferation and survival. Furthermore, depletion of CHKA compromised FGF signaling activity in DU145 cells. We also first time demonstrated that FGFR1 formed complex with CHKA, suggesting that FGFR1 regulated CHKA at the posttranslational level. Together with the previous report that ectopic FGFR1 contributes to PCa progression and metastasis, our results here unravel a novel mechanism by which FGFR1 promotes PCa progression by dysregulating choline metabolism, and that the crosstalk between FGFR1-choline metabolism can be a potential target for managing PCa progression.

FGFR families: biological functions and therapeutic interventions in tumors

“…In prostate cancer, yes‐associated protein (YAP)/T‐box transcription factor 5 activates FGFR1 to mediate resistance to MET inhibitors 176 . FGFR1 has also been shown to be associated with downregulation of choline kinase α and dysregulated choline metabolism, which promotes the progression of prostate cancer 177 . HOTAIR promotes migration and invasion of prostate cancer cells by competitively inhibiting miR‐520b, which indirectly increases the expression of FGFR1 178 .…”

“… 176 FGFR1 has also been shown to be associated with downregulation of choline kinase α and dysregulated choline metabolism, which promotes the progression of prostate cancer. 177 HOTAIR promotes migration and invasion of prostate cancer cells by competitively inhibiting miR‐520b, which indirectly increases the expression of FGFR1. 178 MiR‐1205 directly targets FGFR1 to inhibit colony formation, metastasis, and resistance to cisplatin in gastric cancer cells, while circARVCF reverses this effect.…”

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

“…Multiple carcinogenic signaling pathways and transcription factors associated with oncogenesis activate choline metabolism by affecting enzymes in choline metabolism [ 44 , 45 ]. Crucial metabolic enzymes and transporters such as CHK and CTL1 are potential targets to inhibit choline metabolism for cancer therapy [ 46 , 47 ].…”

MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer

“…Indeed, different studies have shown the role of CHKA in human PCa; however, the molecular mechanisms have not yet been fully elucidated. Recently, in the human DU145 PCa cell line, the presence of a molecular complex involving FGFR1 and CHKA was described by [ 29 ]. FGFR1 promotes PCa progression by dysregulating choline metabolism and CHKA [ 29 ].…”

“…Recently, in the human DU145 PCa cell line, the presence of a molecular complex involving FGFR1 and CHKA was described by [ 29 ]. FGFR1 promotes PCa progression by dysregulating choline metabolism and CHKA [ 29 ]. In this light, the crosstalk between FGFR1–choline metabolism might represent an additional potential target for managing PCa progression.…”