Xu Shanshan, Liu Yuwan, Yang Shizhou, Fei Weidong, Qin Jiale, Lu Weiguo, Xu Junfen
Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, China.
Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, China.
iScience. 2024 Jul 14;27(8):110506. doi: 10.1016/j.isci.2024.110506. eCollection 2024 Aug 16.
Ovarian cancer stem cells (OCSCs) significantly impact the prognosis, chemoresistance, and treatment outcomes in OC. While ferroptosis has been proven effective against OCSCs, the intricate relationship between ferroptosis and OCSCs remains incompletely understood. Here, we enriched ovarian cancer stem-like cells (OCSLCs) through mammosphere culture, as an OCSC model. OCSLCs displayed heightened ferroptosis susceptibility, correlating with elevated FXN levels compared to non-stem OC cells. FXN has recently emerged as a potential regulator in ferroptosis. FXN knockdown diminished stemness marker nanog, sphere-forming ability, increased reactive oxygen species (ROS) generation, and attenuated OCSLCs viability. FXN overexpression exacerbated ferroptosis resistance and reduced RSL3-induced cell death. FXN knockdown impeded OCSLC xenograft tumor growth and exacerbated the degeneration of peroxiredoxin 3 (PRDX3), a mitochondrial antioxidant protein participates in oxidative stress. Thus, elevated FXN in OCSLCs suppresses ROS accumulation, fostering ferroptosis resistance, and regulates the antioxidant protein PRDX3. FXN emerges as a potential therapeutic target for OC.
卵巢癌干细胞（OCSCs）对卵巢癌（OC）的预后、化疗耐药性及治疗结果有显著影响。虽然铁死亡已被证明对OCSCs有效，但铁死亡与OCSCs之间的复杂关系仍未完全明确。在此，我们通过乳腺球培养富集卵巢癌干细胞样细胞（OCSLCs），作为OCSCs模型。与非干细胞性OC细胞相比，OCSLCs对铁死亡的敏感性更高，且与升高的FXN水平相关。FXN最近已成为铁死亡中的一个潜在调节因子。敲低FXN可降低干性标志物nanog、成球能力，增加活性氧（ROS）生成，并减弱OCSLCs的活力。过表达FXN可加剧铁死亡抗性并减少RSL3诱导的细胞死亡。敲低FXN可阻碍OCSLC异种移植瘤的生长，并加剧过氧化物酶体增殖物激活受体3（PRDX3）的退化，PRDX3是一种参与氧化应激的线粒体抗氧化蛋白。因此，OCSLCs中升高的FXN可抑制ROS积累，增强铁死亡抗性，并调节抗氧化蛋白PRDX3。FXN成为OC的一个潜在治疗靶点。
