Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer
Open accessAbstract
Cancer cells must integrate multiple biosynthetic demands to drive indefinite proliferation. How these key cellular processes, such as metabolism and protein synthesis, crosstalk to fuel cancer cell growth is unknown. Here, we uncover the mechanism by which the Myc oncogene coordinates the production of the two most abundant classes of cellular macromolecules, proteins, and nucleic acids in cancer cells. We find that a single rate-limiting enzyme, phosphoribosyl-pyrophosphate synthetase 2 (PRPS2), promotes increased nucleotide biosynthesis in Myc-transformed cells. Remarkably, Prps2 couples protein and nucleotide biosynthesis through a specialized cis-regulatory element within the Prps2 5' UTR, which is controlled by the oncogene and translation initiation factor eIF4E downstream Myc activation. We demonstrate with a Prps2 knockout mouse that the nexus between protein and nucleotide biosynthesis controlled by PRPS2 is crucial for Myc-driven tumorigenesis. Together, these studies identify a translationally anchored anabolic circuit critical for cancer cell survival and an unexpected vulnerability for "undruggable" oncogenes, such as Myc. PAPERFLICK:
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c-myc-regulated targets include PRPS2 and CAD.
“Among the c-myc-regulated targets are phosphoribosyl pyrophosphate synthetase 2 (PRPS2), which catalyzes a first step of purine biosynthesis, as well as carbamoyl phosphate synthetase II (CAD), which initiates the pyrimidine ring-building cascade (Cunningham et al., 2014; Eberhardy and Farnham, 2001; Mannava et al., 2008).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Cunningham et al., 2014
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- Authors
- Cunningham, J. T., Moreno, M. V., Lodi, A., Ronen, S. M., & Ruggero, D.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Ruggero, Davide
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 157
- Issue
- 5
- Pages
- 1088-1103
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4140650
- OpenAlex
- W2073120856
- Cited by
- 260
- References
- 57
- Citations by year
- 2026: 20 · 2025: 18 · 2024: 30 · 2023: 17 · 2022: 24 · 2021: 24 · 2020: 20 · 2019: 23 · 2018: 13 · 2017: 16 · 2016: 25 · 2015: 23 · 2014: 7
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-07-31)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Leukemia and Lymphoma Society
- Gladstone Institutes
- Regeneron Pharmaceuticals
- National Institutes of Health
- University of California, Davis
- National Human Genome Research Institute (U01HG004085, U01HG004080)
- National Cancer Institute (R01 CA130812, R01CA140456, R01CA154915, R01CA154916)
- National Center for Research Resources (U42RR024244)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PRPS2, phosphoribosylpyrophosphate synthetase, MYC oncogene, nucleotide synthesis, protein synthesis, rate-limiting enzyme, eIF4E, translation initiation, anabolic metabolism, carcinogenesis, tumor cell proliferation
- MeSH terms
- Animals, B-Lymphocytes, Base Sequence, Burkitt Lymphoma, Cells, Cultured, Humans, Isoenzymes, Molecular Sequence Data, Nucleotides, Ribose-Phosphate Pyrophosphokinase, Protein Biosynthesis, Proto-Oncogene Proteins c-myc, Mice, Knockout, 5' Untranslated Regions, Eukaryotic Initiation Factor-4E, NIH 3T3 Cells, Cell Line, Tumor, Mice, Embryonic Stem Cells, Gene Knockdown Techniques, Carcinogenesis
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