MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma.
MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma.
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MYCN介导tfrc依赖性铁下垂并揭示神经母细胞瘤的脆弱性。
DOI：
10.1038/s41419-021-03790-w
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发表时间：
2021-05-19
影响因子：
9
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Lu Y;Yang Q;Su Y;Ji Y;Li G;Yang X;Xu L;Lu Z;Dong J;Wu Y;Bei JX;Pan C;Gu X;Li B
MYCN扩增与儿童神经母细胞瘤（NB）的不良预后密切相关。MYCN对NB细胞死亡的调节是一个重要方面，因为它直接导致肿瘤进展和治疗耐药性。然而，MYCN和细胞死亡之间的关系仍然难以捉摸。铁凋亡是一种新发现的细胞死亡模式，其特征是脂质过氧化物积累，可以被GPX4减弱，但MYCN是否以及如何调节铁凋亡尚未完全了解。在这里，我们报告MYCN扩增的NB细胞对GPX4靶向铁凋亡诱导剂敏感。机械地，MYCN表达通过上调TFRC的表达来重编程细胞铁代谢，TFRC编码转铁蛋白受体1作为细胞膜上的关键铁转运蛋白。此外，增加的铁摄取促进不稳定铁池的积累，导致脂质过氧化物产生增加。一致地，NB细胞中TFRC过表达也诱导对GPX4抑制和铁凋亡的选择性敏感性。此外，我们发现MYCN未能改变一般脂质代谢和由系统Xc（−）输入用于谷胱甘肽合成的胱氨酸的量，这两者在替代情况下都有助于铁凋亡。总之，携带MYCN扩增的NB细胞易于经历TFRC上调所赋予的铁凋亡，这表明GPX 4靶向铁凋亡诱导剂或TFRC激动剂可以是治疗MYCN扩增的NB的潜在策略。
MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(−) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.
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影响因子：
5.4
作者：
Huang M;Weiss WA
通讯作者：
Weiss WA
ATF4 和 N-Myc 通过 ASCT2 激活协调 MYCN 扩增的神经母细胞瘤细胞中的谷氨酰胺代谢
影响因子：
7.3
作者：
Ren, Ping;Yue, Ming;Qing, Guoliang
通讯作者：
Qing, Guoliang
影响因子：
9
作者：
通讯作者：
--
影响因子：
30.8
作者：
Durbin AD;Zimmerman MW;Dharia NV;Abraham BJ;Iniguez AB;Weichert-Leahey N;He S;Krill-Burger JM;Root DE;Vazquez F;Tsherniak A;Hahn WC;Golub TR;Young RA;Look AT;Stegmaier K
通讯作者：
Stegmaier K
影响因子：
--
作者：
King, David;Li, Xiao Dun;Bryant, Helen E
通讯作者：
Bryant, Helen E