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Xia, Yingfeng; Ye, Bingwei; Ding, Jane; Yu, Yajie; Alptekin, Ahmet; Thangaraju, Muthusamy; Prasad, Puttur D; Ding, Zhi-Chun; Park, Eun Jeong; Choi, Jeong-Hyeon; Gao, Bei; Fiehn, Oliver; Yan, Chunhong; Dong, Zheng; Zha, Yunhong; Ding, Han-Fei
Cancer research, 08/2019, Letnik: 79, Številka: 15Journal Article
amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to -amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in -amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy. .
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