School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Head and Neck Surgery, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Commun Biol. 2024 Aug 17;7(1):1011. doi: 10.1038/s42003-024-06704-6.
The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating metastasis. However, how FGFR1 contributes to PCa progression is not fully revealed. Here we report that ectopic FGFR1 in PCa cells promotes transferrin receptor 1 (TFR1) expression and expands the labile iron pool (LIP), and vice versa. We further demonstrate that FGFR1 stabilizes iron regulatory proteins 2 (IRP2) and therefore, upregulates TFR1 via promoting IRP2 binding to the IRE of TFR1. Deletion of FGFR1 in DU145 cells decreases the LIP, which potentiates the anticancer efficacy of iron chelator. Intriguingly, forced expression of IRP2 in FGFR1 depleted cells reinstates TFR1 expression and LIP, subsequently restoring the tumorigenicity of the cells. Together, our results here unravel a new mechanism by which FGFR1 drives PCa progression and suggest a potential novel target for PCa therapy.
异位成纤维细胞生长因子受体 1（FGFR1）的获得在前列腺癌（PCa）进展中已有充分记录，特别是在赋予肿瘤生长优势和促进转移方面。然而，FGFR1 如何促进 PCa 的进展尚不完全清楚。在这里，我们报告在 PCa 细胞中异位的 FGFR1 促进转铁蛋白受体 1（TFR1）的表达并扩大不稳定铁池（LIP），反之亦然。我们进一步证明 FGFR1 通过促进 IRP2 与 TFR1 的 IRE 结合来稳定铁调节蛋白 2（IRP2），从而上调 TFR1。在 DU145 细胞中删除 FGFR1 会减少 LIP，从而增强铁螯合剂的抗癌功效。有趣的是，在 FGFR1 耗尽的细胞中强制表达 IRP2 可重新表达 TFR1 和 LIP，随后恢复细胞的致瘤性。总之，我们的研究结果揭示了 FGFR1 驱动 PCa 进展的新机制，并为 PCa 治疗提供了一个新的潜在靶点。
