PRPS2 directly couples MYC-dependent activation of protein synthesis with nucleotide metabolism.

  • Major finding: PRPS2 directly couples MYC-dependent activation of protein synthesis with nucleotide metabolism.

  • Concept: MYC drives translation of PRPS2, a rate-limiting enzyme in nucleotide biosynthesis.

  • Impact: PRPS2 inhibition could exploit metabolic vulnerabilities of MYC-overexpressing cancer cells.

Cancer cells must meet enhanced protein and nucleic acid biosynthetic demands to drive rapid proliferation, but how these cellular processes are coordinated is not fully understood. By examining the metabolic profiles of B cells from a MYC-driven mouse model of Burkitt lymphoma, Cunningham and colleagues found that the elevation of purine nucleotide pathway metabolites could be specifically rescued by haploinsufficiency of the ribosomal gene Rpl24, implying that MYC-dependent enhancement of protein synthesis is linked to nucleotide metabolism. Interestingly, MYC overexpression induced the upregulation of phosphoribosyl-pyrophosphate synthetase 2 (PRPS2), a rate-limiting enzyme of nucleotide biosynthesis, and modulation of PRPS2 levels by either knockdown or overexpression respectively inhibited or potentiated nucleotide production, suggesting that PRPS2 is necessary and sufficient to regulate the overall rate of purine metabolism. Serum stimulation induced a rapid shift of Prps2 mRNA to polyribosomes and an increase in PRPS2 protein, but not mRNA, levels, signifying that Prps2 is translationally regulated. Consistent with these findings, inhibition of eIF4E, a regulator of translation initiation and a direct target of MYC, blocked PRPS2 upregulation in response to serum stimulation or MYC overexpression, and an eIF4E-responsive pyrimidine-rich translational element (PRTE) within the 5′ UTR of Prps2 was sufficient for translational regulation, indicating that the PRTE in Prps2 mRNA acts as a sensor that directly couples MYC-driven protein synthesis with nucleotide production. Notably, PRPS2 knockdown displayed synthetic lethality in MYC-transformed cells, significantly delayed lymphomagenesis and induced regression of established tumors in vivo, and markedly increased apoptosis in MYC-dependent human cancer cell lines. Of note, PRPS2 was not essential in normal cells, suggesting that there may be a therapeutic window for targeting PRPS2. These findings reveal a mechanism by which increased protein synthesis and nucleotide metabolism are coordinated to sustain homeostasis in MYC-overexpressing cancer cells that may be a therapeutic target in MYC-driven cancers.

Cunningham JT, Moreno MV, Lodi A, Ronen SM, Ruggero D. Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 2014;157:1088–103.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2014 American Association for Cancer Research.
2014