title: Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer.
abstract: 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:
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Cunningham
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Moreno
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lodi
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: davide.ruggero@ucsf.edu.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000378:metabolism; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053595:Embryonic Stem Cells; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009711:Nucleotides / Q000096:biosynthesis*; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D039561:Eukaryotic Initiation Factor-4E; D007527:Isoenzymes; D009711:Nucleotides; D016271:Proto-Oncogene Proteins c-myc; D012268:Ribose-Phosphate Pyrophosphokinase