Fabiana Marini ¹,², Nicole Rodríguez ¹,², Roberto Angeli ¹,², Gerardo Caussade ¹,², Kiara Ayuso ¹,²,

Alejandra Vazquez ¹,² and Nataliya Chorna ¹,³

1 PR-INBRE Metabolomics Research Core, University of Puerto Rico, School of Medicine, SJ, PR

2 Department of Biology, University of Puerto Rico, Rio Piedras Campus, SJ, PR

3 Department of Biochemistry, University of Puerto Rico, School of Medicine, SJ, PR

Neuroblastoma is a heterogeneous and highly malignant pediatric tumor derived from the neural crest. Therapy for high-risk patients includes the differentiating agent retinoic acid (RA); however, more than 50% of patients relapse, which could be due to, at least in part, the fact that neuroblastoma constitutes morphologically distinct phenotypes: neuroblast-like and epithelial-like cells. To date, the biochemical mechanisms that lead to the relapse after RA therapy are not completely elucidated. Given that epithelial-like cells could not undergo neuronal differentiation, we hypothesized that they confront RA metabolic reprogramming via activation of a specific biosynthetic challenge sufficient for their continued growth, which could be a reason for the relapsing of the disease. In our study, we applied GC/MS-based metabolomics to analyze the effects of RA treatment on SH-SY5Y neuroblastoma cells. Mapping of significantly altered metabolites on known pathways reveals the beneficial effects of RA on shifting the energy metabolism from glycolysis to oxidative phosphorylation, a dramatic decrease in fatty acid synthesis and elevation of redox homeostasis. We also found RA-induced elevation in the serineglycine- one-carbon biosynthetic pathway. While this pathway is crucial to encounter the consequences of oxidative stress due to metabolic reprogramming from glycolysis to oxidative phosphorylation, it is also an essential component for neuroblastoma cell growth. An increase in its flux could maintain epithelial-like neuroblastoma cells in a proliferative state with blocked differentiation and trigger the relapse after RA therapy. Taken together, our study highlights the therapeutic potential of targeting the serine-glycine-one-carbon biosynthetic pathway in combination with RA to improve the outcome of neuroblastoma treatment. This work was supported by NIH/NIGMS-PRINBRE Grant 5P20GM103475

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