Objective and design

Ovarian cancer is the major cause of death in gynecologic diseases worldwide. Ferroptosis, a nonapoptotic form of cell death, is featured by accumulation of iron-based lipid peroxidation. The elevated iron level and malondialdehyde (MDA) in ovarian cancer cells suggest more vulnerable to ferroptosis, nevertheless, ferroptosis is not observed in ovarian cancer cells. Glutathione peroxidase 4 (GPX4) is a critical regulator of ferroptosis.

Methods

We determined whether GPX4 knockdown could induce ferroptosis to prevent cell proliferation in ovarian cancer. Human ovarian cancer cells and normal human ovarian epithelial cell line IOSE-80 were cultured and administrated with deferoxamine (DFO) or ferric ammonium citrate (FAC). GPX4 knockdown was established for investigating the functions of GPX4 in ovarian cancer cells and in tumor xenograft mice.

Results

A positively correlation was showed among the levels of GPX4, iron and cell proliferation. Chelation of intracellular iron by DFO disrupted intracellular iron level and was detrimental to ovarian cancer cell survival. FAC-induced elevation of intracellular iron inhibited proliferation, aggravated apoptosis, boosted inflammation and suppressed lipid peroxide reducibility in ovarian cancer cells. Knockdown of GPX4 had similar effects with FAC in ovarian cancer cells. Inhibition of GPX4 suppressed tumor growth, induced ferroptosis, accelerated cell apoptosis, reduced Fe³⁺ accumulation and suppressed lipid peroxide reducibility in tumor bearing mice.

Conclusion

We demonstrate the significance of GPX4 and intracellular iron level in ovarian cancer cells. Importantly, inhibition of GPX4 interferes with both intracellular iron homeostasis and lipid peroxide reducibility, inducing ferroptosis and exerting anti-cancer effect, which can be a potential effective strategy for ovarian cancer therapy.

中文翻译：

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卵巢癌细胞谷胱甘肽过氧化物酶4和细胞内铁水平的意义——“利用”铁死亡机制

目标与设计

卵巢癌是全球妇科疾病死亡的主要原因。铁死亡是一种非凋亡形式的细胞死亡，其特征是铁基脂质过氧化的积累。卵巢癌细胞中铁水平和丙二醛（MDA）升高表明更容易发生铁死亡，然而，在卵巢癌细胞中没有观察到铁死亡。谷胱甘肽过氧化物酶 4 (GPX4) 是铁死亡的关键调节因子。

方法

我们确定了 GPX4 敲低是否可以诱导铁死亡以防止卵巢癌中的细胞增殖。用去铁胺（DFO）或柠檬酸铁铵（FAC）培养人卵巢癌细胞和正常人卵巢上皮细胞系IOSE-80。GPX4 敲低是为了研究 GPX4 在卵巢癌细胞和肿瘤异种移植小鼠中的功能而建立的。

结果

GPX4、铁和细胞增殖水平呈正相关。DFO 对细胞内铁的螯合破坏了细胞内铁水平，不利于卵巢癌细胞的存活。FAC 诱导的细胞内铁升高可抑制卵巢癌细胞的增殖、加重细胞凋亡、促进炎症并抑制脂质过氧化物的还原性。GPX4 的敲低与 FAC 在卵巢癌细胞中的作用相似。抑制 GPX4 可抑制肿瘤生长、诱导铁死亡、加速细胞凋亡、减少 Fe ³⁺积累并抑制荷瘤小鼠的脂质过氧化物还原性。

结论

我们证明了 GPX4 和卵巢癌细胞中细胞内铁水平的重要性。重要的是，抑制 GPX4 会干扰细胞内铁稳态和脂质过氧化物的还原性，诱导铁死亡并发挥抗癌作用，这可能是卵巢癌治疗的潜在有效策略。