Down-Regulation of Phosphoribosyl Pyrophosphate Synthetase 1 Inhibits Neuroblastoma Cell Proliferation

Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is a key enzyme in de novo nucleotide synthesis and nucleotide salvage synthesis pathways that are critical for purine and pyrimidine biosynthesis. Abnormally high expression of PRPS1 can cause many diseases, including hearing loss, hypotonia, and ataxia, in addition to being associated with neuroblastoma. However, the role of PRPS1 in neuroblastoma is still unclear. In this study, we found that PRPS1 was commonly expressed in neuroblastoma cells and was closely related to poor prognosis for cancer. Furthermore, down-regulation of PRPS1 inhibited neuroblastoma cell proliferation and tumor growth in vitro and in vivo via disturbing DNA synthesis. This study provides new insights into the treatment of neuroblastoma patients and new targets for drug development.

Patient-derived phosphoribosyl pyrophosphate synthetase mutations in Drosophila result in autophagy and lysosome dysfunction

Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in nucleotide metabolism. While missense mutations of PRPS1 have been identified in neurological disorders such as Arts syndrome, little is known on how they contribute to pathogenesis. We engineered Drosophila PRPS (dPRPS) alleles that carry patient-derived PRPS missense mutations. Although dPRPS mutant flies develop normally, they have profound defects in autophagy induction and lysosome function. Consequently, dPRPS flies are sensitive to nutrient deprivation as they are unable to break down lipid storage by macroautophagy. In addition, we provide evidence showing that dRPPS is required for proper cellular response to oxidative stress, providing a possible mechanism by which PRPS1 dysfunction contributes to neurological disorders.