Wang Ning, Chen Min, Wu Manting, Liao Yuan, Xia Qing, Cai Zheyou, He Chengsi, Tang Qing, Zhou Yuan, Zhao Lei, Zou Zhengzhi, Chen Yibing, Han Liping
Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China.
The Fourth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511300, China.
Free Radic Biol Med. 2025 Feb 16;228:1-13. doi: 10.1016/j.freeradbiomed.2024.12.040. Epub 2024 Dec 18.
Ovarian cancer remains a significant challenge due to the lack of effective treatment and the resistance to conventional therapies. Ferroptosis, a form of regulated cell death characterized by iron-depend and lipid peroxidation, has emerged as a potential therapeutic target in cancer. Ovarian cancer has been reported to exert an "iron addiction" phenotype which makes it is susceptible to ferroptosis inducers. However, we found here that high-adhesion ovarian cancer cells were resistant to ferroptosis. Mechanistically, by PCR array, we identified junctional adhesion molecule 3 (JAM3) as a key mediator of ferroptosis resistance in high-adhesion ovarian cancer cells. Knockdowning and blocking JAM3 sensitized cancer cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance to these agents. In addition, JAM3 also promoted ovarian cancer cells resistance to chemotherapeutic agent cisplatin in vitro and in vivo by inhibiting ferroptosis. Furthermore, we demonstrated that JAM3 promoted ferroptosis resistance through NRF2-induced upregulation of FSP1, a critical suppressor of lipid peroxidation. Inhibition of the NRF2/FSP1 pathway eliminated high-adhesion, JAM3 overexpressed ovarian cancer cells resistance to ferroptosis, and decreased cancer cells resistance to cisplatin. Moreover, JAM3 high expression was associated with poor prognosis in patients with ovarian cancer. Altogether, this study provided novel insights into the molecular mechanisms underlying ferroptosis resistance and identify JAM3 as a potential therapeutic target for combating drug resistance in ovarian cancer.
由于缺乏有效的治疗方法以及对传统疗法的耐药性，卵巢癌仍然是一个重大挑战。铁死亡是一种以铁依赖性和脂质过氧化为特征的程序性细胞死亡形式，已成为癌症潜在的治疗靶点。据报道，卵巢癌具有“铁成瘾”表型，这使其易受铁死亡诱导剂的影响。然而，我们在此发现高黏附性卵巢癌细胞对铁死亡具有抗性。从机制上讲，通过PCR阵列，我们确定连接黏附分子3（JAM3）是高黏附性卵巢癌细胞中铁死亡抗性的关键介质。敲低和阻断JAM3可使癌细胞对铁死亡诱导剂RSL3和埃拉斯汀敏感，而JAM3过表达则赋予对这些药物的抗性。此外，JAM3还通过抑制铁死亡在体外和体内促进卵巢癌细胞对化疗药物顺铂的抗性。此外，我们证明JAM3通过NRF2诱导的脂质过氧化关键抑制因子FSP1的上调来促进铁死亡抗性。抑制NRF2/FSP1途径消除了高黏附性、JAM3过表达的卵巢癌细胞对铁死亡的抗性，并降低了癌细胞对顺铂的抗性。此外，JAM3高表达与卵巢癌患者的不良预后相关。总之，本研究为铁死亡抗性的分子机制提供了新的见解，并确定JAM3为对抗卵巢癌耐药性的潜在治疗靶点。
