文章目录

MYCN介导半胱氨酸成瘾并使神经母细胞瘤对铁下垂敏感

原文发布日期：2022-04-28

英文摘要：

摘要翻译：

原文链接：

文章：

MYCN介导半胱氨酸成瘾并使神经母细胞瘤对铁下垂敏感

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis

原文发布日期：2022-04-28

英文摘要：

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.

摘要翻译：

MYC转录因子家族成员的异常表达在许多人类癌症中预示着不良的临床结果。致癌的MYC通过显著改变代谢，并通过抗氧化应答维持红ox平衡。我们发现，MYCN诱导在半胱氨酸缺乏时脂质过氧化反应，并使细胞对铁依赖性自噬易感。这种自噬是氧非程序性的细胞死亡类型。MYCN增强的儿童神经母细胞需要大量半胱氨酸来支持蛋白质合成，其需求通过转运和转硫过程得到满足。当转运能力受限时，半胱氨酸用于蛋白质合成而以GSH水平触发自噬性细胞死亡，并可能解释低风险神经母癌自发退癌的现象。通过药物抑制转运及转硫并结合GPX4失活，在MYCN增强的神经母细胞体外模型中实现了肿瘤退化。这些发现表明，联合作用于多个自噬靶点是一个有潜力的治疗策略来治疗 MYC增强的恶性肿瘤。