Crosstalk of FGFR1 signaling and choline metabolism promotes cell proliferation and survival in prostate cancer cells
Crosstalk of FGFR1 signaling and choline metabolism promotes cell proliferation and survival in prostate cancer cells
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DOI：
10.1002/ijc.33922
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发表时间：
2022-01-18
影响因子：
6.4
通讯作者：
Wang, Cong
中科院分区：
文献类型：
--
作者：
Fan, Zhichao;Ma, Jisheng;Wang, Cong
异位I型成纤维细胞生长因子受体（FGFR 1）的获得是前列腺癌（PCa）的常见特征，前列腺癌是男性中最常见的诊断性癌症。然而，异位FGFR 1如何促进PCa进展尚不清楚。在我们的研究中，我们发现DU 145人PCa细胞中FGFR 1的消融改变了细胞代谢产物谱。在这些变化中，胆碱代谢特征是FGFR 1消融最显著的改变。详细的表征表明，消融FGFR 1改变了多种胆碱代谢酶的表达。在FGFR 1调节的胆碱代谢酶的变化中，胆碱激酶α（CHKA）的下调是最突出的变化，其将游离胆碱磷酸化为磷酸胆碱。FGFR 1的消融减弱了胆碱促进细胞增殖和存活的活性。此外，CHKA的消耗损害了DU 145细胞中的FGF信号传导活性。我们还首次证实了FGFR 1与CHKA形成复合物，提示FGFR 1在翻译后水平调控CHKA。结合之前的报道，异位FGFR 1有助于PCa进展和转移，我们的研究结果揭示了FGFR 1通过胆碱代谢失调促进PCa进展的新机制，并且FGFR 1-胆碱代谢之间的串扰可能是管理PCa进展的潜在靶点。
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 alpha (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.