International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, PR China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, PR China.
College of Chemistry and Life Science, Zhejiang Normal University, Jinhua, 321004, PR China.
Free Radic Biol Med. 2022 Mar;182:79-92. doi: 10.1016/j.freeradbiomed.2022.02.023. Epub 2022 Feb 24.
Ovarian cancer has the most mortality of all gynecologic malignancies. High-grade serous ovarian carcinoma (HGSOC) is the most common and deadly type of ovarian cancer. Tumor recurrence occurs due to the emergence of chemotherapy resistance. Thus, searching for new therapeutic strategies is essential for the management of ovarian cancer. Deregulation of iron metabolism can be used by ovarian cancer cells to survive, proliferate and metastasize. Here we report that sodium molybdate, a soluble molybdenum (Mo) compound, induces the elevation of the labile iron pool (LIP) in ovarian cancer cells, correlated with the down-regulation of genes involved in extracellular matrix organization. Sodium molybdate also induces depletion of glutathione (GSH) through mediating the production of nitric oxide (NO). Elevation of LIP and depletion of GSH promote the ferroptosis of ovarian cancer cells. Meanwhile, nitric oxide induces mitochondrial damage through inhibiting mitochondrial aconitase activity, ATP production, and mitochondrial membrane potential, leading to apoptosis of ovarian cancer cells. In vivo study shows that sodium molybdate reduces tumor burden in nude mice. Xenografts treated with sodium molybdate are characterized by obvious iron accumulation, increased expression of the iron storage protein ferritin, and lipid peroxide product 4-hydroxynonenal. In addition, an elevated percentage of apoptotic cells is observed in xenografts treated with sodium molybdate. Taken together, these results demonstrate that sodium molybdate can induce both ferroptosis and apoptosis of ovarian cancer cells, making it a potential therapeutic candidate for ovarian cancer.
卵巢癌是所有妇科恶性肿瘤中死亡率最高的。高级别浆液性卵巢癌（HGSOC）是最常见和最致命的卵巢癌类型。肿瘤复发是由于化疗耐药的出现。因此，寻找新的治疗策略对于卵巢癌的治疗至关重要。铁代谢失调可被卵巢癌细胞用来存活、增殖和转移。在这里，我们报告钼酸钠，一种可溶性钼（Mo）化合物，可诱导卵巢癌细胞中不稳定铁池（LIP）的升高，与细胞外基质组织相关基因的下调相关。钼酸钠还通过介导一氧化氮（NO）的产生来耗竭谷胱甘肽（GSH）。LIP 的升高和 GSH 的耗竭促进了卵巢癌细胞的铁死亡。同时，一氧化氮通过抑制线粒体三羧酸循环酶活性、ATP 产生和线粒体膜电位诱导线粒体损伤，导致卵巢癌细胞凋亡。体内研究表明，钼酸钠可减少裸鼠的肿瘤负担。用钼酸钠处理的异种移植物的特征是明显的铁积累、铁储存蛋白铁蛋白的表达增加以及脂质过氧化物产物 4-羟基壬烯醛。此外，在用钼酸钠处理的异种移植物中观察到凋亡细胞的百分比升高。总之，这些结果表明钼酸钠可以诱导卵巢癌细胞的铁死亡和细胞凋亡，使其成为卵巢癌的潜在治疗候选物。
