Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, P. R. China.
The Animal Laboratory Center, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, P. R. China.
Cell Death Dis. 2024 Apr 18;15(4):279. doi: 10.1038/s41419-024-06671-0.
Cisplatin (DDP)-based chemoradiotherapy is one of the standard treatments for nasopharyngeal carcinoma (NPC). However, the sensitivity and side effects of DDP to patients remain major obstacles for NPC treatment. This research aimed to study DDP sensitivity regulated by cancer-associated fibroblasts (CAFs) through modulating ferroptosis. We demonstrated that DDP triggered ferroptosis in NPC cells, and it inhibited tumor growth via inducing ferroptosis in xenograft model. CAFs secreted high level of FGF5, thus inhibiting DDP-induced ferroptosis in NPC cells. Mechanistically, FGF5 secreted by CAFs directly bound to FGFR2 in NPC cells, leading to the activation of Keap1/Nrf2/HO-1 signaling. Rescued experiments indicated that FGFR2 overexpression inhibited DDP-induced ferroptosis, and CAFs protected against DDP-induced ferroptosis via FGF5/FGFR2 axis in NPC cells. In vivo data further showed the protective effects of FGF5 on DDP-triggered ferroptosis in NPC xenograft model. In conclusion, CAFs inhibited ferroptosis to decrease DDP sensitivity in NPC through secreting FGF5 and activating downstream FGFR2/Nrf2 signaling. The therapeutic strategy targeting FGF5/FGFR2 axis from CAFs might augment DDP sensitivity, thus decreasing the side effects of DDP in NPC treatment.
顺铂（DDP）为基础的放化疗是鼻咽癌（NPC）的标准治疗方法之一。然而，DDP 对患者的敏感性和副作用仍然是 NPC 治疗的主要障碍。本研究旨在通过调节铁死亡研究癌症相关成纤维细胞（CAFs）调节 DDP 敏感性。我们表明 DDP 触发 NPC 细胞中的铁死亡，并通过在异种移植模型中诱导铁死亡来抑制肿瘤生长。CAFs 分泌高水平的 FGF5，从而抑制 NPC 细胞中 DDP 诱导的铁死亡。在机制上，CAFs 分泌的 FGF5 直接与 NPC 细胞中的 FGFR2 结合，导致 Keap1/Nrf2/HO-1 信号通路的激活。挽救实验表明，FGFR2 过表达抑制了 DDP 诱导的铁死亡，并且 CAFs 通过 FGF5/FGFR2 轴在 NPC 细胞中保护免受 DDP 诱导的铁死亡。体内数据进一步显示了 FGF5 在 NPC 异种移植模型中对 DDP 触发的铁死亡的保护作用。总之，CAFs 通过分泌 FGF5 并激活下游 FGFR2/Nrf2 信号来抑制铁死亡，从而降低 NPC 中 DDP 的敏感性。针对 CAFs 中 FGF5/FGFR2 轴的治疗策略可能会增强 DDP 的敏感性，从而降低 NPC 治疗中 DDP 的副作用。
