Abstract：
Ovarian cancer is a malignant tumor originating from the ovary, characterized by its high mortality rate and propensity for recurrence. In some patients, especially those with recurrent cancer, conventional treatments such as surgical resection or standard chemotherapy yield suboptimal results. Consequently, there is an urgent need for novel anti-cancer therapeutic strategies. Ferroptosis is a distinct form of cell death separate from apoptosis. Ferroptosis inducers have demonstrated promising potential in the treatment of ovarian cancer, with evidence indicating their ability to enhance ovarian cancer cell sensitivity to cisplatin. However, resistance of cancer cells to ferroptosis still remains an inevitable challenge. Here, we analyzed genome-scale CRISPR-Cas9 loss-of function screens and identified PAX8 as a ferroptosis resistance protein in ovarian cancer. We identified PAX8 as a susceptibility gene in GPX4-dependent ovarian cancer. Depletion of PAX8 rendered GPX4-dependent ovarian cancer cells significantly more sensitive to GPX4 inhibitors. Additionally, we found that PAX8 inhibited ferroptosis in ovarian cancer cells. Combined treatment with a PAX8 inhibitor and RSL3 suppressed ovarian cancer cell growth, induced ferroptosis, and was validated in a xenograft mouse model. Further exploration of the molecular mechanisms underlying PAX8 inhibition of ferroptosis mutations revealed upregulation of glutamate-cysteine ligase catalytic subunit (GCLC) expression. GCLC mediated the ferroptosis resistance induced by PAX8 in ovarian cancer. In conclusion, our study underscores the pivotal role of PAX8 as a therapeutic target in GPX4-dependent ovarian cancer. The combination of PAX8 inhibitors such as losartan and captopril with ferroptosis inducers represents a promising new approach for ovarian cancer therapy.
摘要：
卵巢癌是起源于卵巢的恶性肿瘤，其特点是高死亡率和复发倾向。在一些患者中，尤其是那些癌症复发的患者，常规治疗，如手术切除或标准化疗产生次优的结果。因此,迫切需要新的抗癌治疗策略。铁凋亡是与细胞凋亡分开的细胞死亡的独特形式。Ferroposis诱导剂在卵巢癌的治疗中显示出有希望的潜力，有证据表明它们能够增强卵巢癌细胞对顺铂的敏感性。然而,癌细胞对铁凋亡的抗性仍然是一个不可避免的挑战。这里,我们分析了基因组规模的CRISPR-Cas9功能缺失筛选,并将PAX8鉴定为卵巢癌的铁凋亡抗性蛋白.我们确定PAX8是GPX4依赖性卵巢癌的易感基因。PAX8的耗尽使得GPX4依赖性卵巢癌细胞对GPX4抑制剂显著更敏感。此外,我们发现PAX8抑制卵巢癌细胞的铁凋亡。与PAX8抑制剂和RSL3联合治疗抑制卵巢癌细胞生长，诱导铁性凋亡，并在异种移植小鼠模型中进行了验证。对PAX8抑制铁凋亡突变的分子机制的进一步探索揭示了谷氨酸-半胱氨酸连接酶催化亚基（GCLC）表达的上调。GCLC介导PAX8诱导的卵巢癌细胞凋亡抵抗。总之,我们的研究强调了PAX8作为GPX4依赖性卵巢癌治疗靶点的关键作用.PAX8抑制剂如氯沙坦和卡托普利与铁凋亡诱导剂的组合代表了卵巢癌治疗的有希望的新方法。
