Wang Yue, Ji Huilin, Yang Tianpeng, Liu Yi, He Xiang, Jiang Xinyue, Lu Zipeng, Han Liu, Liu Xiaodong, Ma Shumei
School of Public Health, Wenzhou Medical University, Wenzhou, China.
South Zhejiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou, China.
Cell Death Discov. 2025 Apr 22;11(1):191. doi: 10.1038/s41420-025-02388-x.
Cervical squamous cell carcinoma (CESC) is one of the most common cancers in women, and radiotherapy has been used as a primary treatment. However, its efficacy is limited by intrinsic and acquired radiation resistance. Our previous study demonstrated that Deoxycytidine kinase (dCK) inhibits ionizing radiation (IR)-induced cell death, including apoptosis and mitotic catastrophe, and dCK is a HSP90-interacting protein by mass spectrometry and co-immunoprecipitation assay. In the present study, we found that dCK inhibited IR-induced ferroptosis by increasing the activity and stability of SLC7A11. Using the E3 ubiquitin ligase database (UbiBrowser), we predicted NEDD4L as a potential ubiquitin ligase of dCK, and WWP1/2 as potential ubiquitin ligases of NEDD4L, respectively. These predictions were subsequently verified through a ubiquitination IP assay. Our findings indicate that HSP90 regulates dCK stability by inhibiting NEDD4L through the recruitment of ubiquitin ligases WWP1/2. In summary, our study reveals the HSP90-WWP1/WWP2-NEDD4L-dCK-SLC7A11 axis as a critical regulator of IR-induced ferroptosis in HeLa cells. These findings provide valuable insights into potential strategies for the radiosensitization of cervical cancer.
宫颈鳞状细胞癌(CESC)是女性中最常见的癌症之一,放射治疗一直被用作主要治疗方法。然而,其疗效受到内在和获得性放射抗性的限制。我们之前的研究表明,脱氧胞苷激酶(dCK)抑制电离辐射(IR)诱导的细胞死亡,包括凋亡和有丝分裂灾难,并且通过质谱和免疫共沉淀分析发现dCK是一种与热休克蛋白90(HSP90)相互作用的蛋白。在本研究中,我们发现dCK通过增加溶质载体家族7成员11(SLC7A11)的活性和稳定性来抑制IR诱导的铁死亡。使用E3泛素连接酶数据库(UbiBrowser),我们分别预测NEDD4样泛素蛋白连接酶(NEDD4L)是dCK的潜在泛素连接酶,而WWP1/2是NEDD4L的潜在泛素连接酶。随后通过泛素化免疫沉淀试验验证了这些预测。我们的研究结果表明,HSP90通过募集泛素连接酶WWP1/2抑制NEDD4L来调节dCK的稳定性。总之,我们的研究揭示了HSP90-WWP1/WWP2-NEDD4L-dCK-SLC7A11轴是HeLa细胞中IR诱导的铁死亡的关键调节因子。这些发现为宫颈癌放射增敏的潜在策略提供了有价值的见解。