MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
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DOI：
10.1038/s43018-022-00355-4
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发表时间：
2022-04
期刊：
影响因子：
22.7
通讯作者：
Westermann, Frank
中科院分区：
文献类型：
--
作者：
Alborzinia, Hamed;Florez, Andres F.;Kreth, Sina;Brueckner, Lena M.;Yildiz, Umut;Gartlgruber, Moritz;Odoni, Dorett, I;Poschet, Gernot;Garbowicz, Karolina;Shao, Chunxuan;Klein, Corinna;Meier, Jasmin;Zeisberger, Petra;Nadler-Holly, Michal;Ziehm, Matthias;Paul, Franziska;Burhenne, Juergen;Bell, Emma;Shaikhkarami, Marjan;Wuerth, Roberto;Stainczyk, Sabine A.;Wecht, Elisa M.;Kreth, Jochen;Buettner, Michael;Ishaque, Naveed;Schlesner, Matthias;Nicke, Barbara;Stresemann, Carlo;Llamazares-Prada, Maria;Reiling, Jan H.;Fischer, Matthias;Amit, Ido;Selbach, Matthias;Herrmann, Carl;Woelfl, Stefan;Henrich, Kai-Oliver;Hoefer, Thomas;Trumpp, Andreas;Westermann, Frank
MYC 转录因子家族成员的异常表达预示着许多人类癌症的临床结果不佳。致癌 MYC 深刻改变新陈代谢并介导抗氧化反应以维持氧化还原平衡。在这里，我们发现，MYCN 在半胱氨酸（谷胱甘肽（GSH）生物合成的限速氨基酸）耗尽时诱导大量脂质过氧化，并使细胞对铁死亡（一种氧化性、非凋亡性和铁依赖性细胞死亡类型）敏感。 MYCN 扩增的儿童神经母细胞瘤对半胱氨酸的高需求通过摄取和转硫来满足。当摄取受到限制时，半胱氨酸用于蛋白质合成的维持会以谷胱甘肽（GSH）触发铁死亡为代价，并可能有助于低风险神经母细胞瘤的自发肿瘤消退。在原位 MYCN 扩增神经母细胞瘤模型中，胱氨酸摄取和转硫作用的药理抑制与 GPX4 灭活相结合导致肿瘤缓解。这些发现提供了联合多个铁死亡靶点作为治疗侵袭性 MYCN 扩增肿瘤的有前途的治疗策略的概念证明。 Alborzinia 等。报道称，MYCN 扩增的神经母细胞瘤在细胞内半胱氨酸缺失的情况下会发生铁死亡，这表明半胱氨酸耗尽和伴随的 GPX4 失活相结合是一种潜在的治疗方法。
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. Alborzinia et al. report that MYCN-amplified neuroblastoma undergoes ferroptosis in the absence of intracellular cysteine, suggesting a combination of cysteine depletion and concomitant GPX4 inactivation as a potential therapeutic approach.
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影响因子：
9
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
通讯作者：
Li B
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
5.9
作者：
Alborzinia, Named;Ignashkova, Tatiana I.;Reiling, Jan H.
通讯作者：
Reiling, Jan H.
影响因子：
64.5
作者：
McDonald, E. Robert, III;de Weck, Antoine;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
12.4
作者：
Afanasyeva, E. A.;Mestdagh, P.;Westermann, F.
通讯作者：
Westermann, F.