Singh Tanu, Beatty Alexander, Peterson Jeffrey R
Cancer Signaling & Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Cell Death Discov. 2022 May 6;8(1):253. doi: 10.1038/s41420-022-01044-y.
Ferroptosis is a caspase-independent form of regulated cell death strongly linked to the accumulation of reactive lipid hydroperoxides. Lipid hydroperoxides are neutralized in cells by glutathione peroxidase 4 (GPX4) and inhibitors of GPX4 are potent ferroptosis inducers with therapeutic potential in cancer. Here we report that siRNA-mediated silencing of the AMPK-related kinase NUAK2 suppresses cell death by small-molecule inducers of ferroptosis but not apoptosis. Mechanistically we find that NUAK2 suppresses the expression of GPX4 at the RNA level and enhances ferroptosis triggered by GPX4 inhibitors in a manner independent of its kinase activity. NUAK2 is amplified along with MDM4 in a subset of breast cancers, particularly the claudin-low subset, suggesting that this may predict vulnerability to GPX4 inhibitors. These findings identify a novel pathway regulating GPX4 expression as well as ferroptotic sensitivity with potential as a biomarker of breast cancer patients that might respond to GPX4 inhibition as a therapeutic strategy.
铁死亡是一种不依赖半胱天冬酶的程序性细胞死亡形式，与活性脂质氢过氧化物的积累密切相关。脂质氢过氧化物在细胞中由谷胱甘肽过氧化物酶4（GPX4）中和，GPX4抑制剂是有效的铁死亡诱导剂，在癌症治疗中具有潜力。在此我们报告，RNA干扰介导的AMPK相关激酶NUAK2沉默可抑制小分子铁死亡诱导剂引起的细胞死亡，但不抑制凋亡。从机制上我们发现，NUAK2在RNA水平上抑制GPX4的表达，并以一种不依赖其激酶活性的方式增强GPX4抑制剂引发的铁死亡。在一部分乳腺癌中，特别是claudin低表达亚型中，NUAK2与MDM4一起扩增，这表明这可能预示着对GPX4抑制剂的敏感性。这些发现确定了一条调节GPX4表达以及铁死亡敏感性的新途径，有可能作为乳腺癌患者的生物标志物，这些患者可能对作为治疗策略的GPX4抑制有反应。
