Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway.

Cancer research (2019-05-16)
Yingfeng Xia, Bingwei Ye, Jane Ding, Yajie Yu, Ahmet Alptekin, Muthusamy Thangaraju, Puttur D Prasad, Zhi-Chun Ding, Eun Jeong Park, Jeong-Hyeon Choi, Bei Gao, Oliver Fiehn, Chunhong Yan, Zheng Dong, Yunhong Zha, Han-Fei Ding

MYCN 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 MYCN 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 MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-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.See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818.

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D-(+)-Glucose solution, 45% in H2O, sterile-filtered, BioXtra, suitable for cell culture
ANTI-FLAG® antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
NCT-503, ≥98% (HPLC)
CBR-5884, ≥98% (HPLC)
NCT-503 Inactive Control, ≥98% (HPLC)

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