title: Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC.
abstract: In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS). Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less well-recognized, glutamate can also be converted to proline through Δ(1)-pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b* mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b* is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS. Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through up-regulating miR-23b*. The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects. Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYC-induced proline biosynthesis from glutamine was directly confirmed using (13)C,(15)N-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism. Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies.
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702, USA. liuwei7997@gmail.com
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Anne
authors.initials: A
authors.lastname: Le
authors.forename: Chad
authors.initials: C
authors.lastname: Hancock
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Lane
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Teresa W-M
authors.initials: TW
authors.lastname: Fan
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
mesh_terms: D015153:Blotting, Western; D002247:Carbon Isotopes / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009587:Nitrogen Isotopes / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D011392:Proline / Q000378:metabolism*; D011394:Proline Oxidase / Q000378:metabolism*; D011762:Pyrroline Carboxylate Reductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D002247:Carbon Isotopes; D004268:DNA-Binding Proteins; D005973:Glutamine; D035683:MicroRNAs; D009587:Nitrogen Isotopes; D011392:Proline; D011394:Proline Oxidase; D011762:Pyrroline Carboxylate Reductases; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase; C552430:MIRN23a microRNA, human; C116115:MYCBP protein, human