Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC
Open accessAbstract
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.
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PYCR1 expression is upregulated by c-myc.
“The expression of the principal enzyme in proline biosynthesis, pyrroline-5-carboxylate reductase (PYCR1), is upregulated by c-myc (Liu et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Liu et al., 2012
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- Authors
- Liu, W., Le, A., Hancock, C., Lane, A. N., Dang, C. V., Fan, T. W.-M., & Phang, J. M.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- Johns Hopkins University (US)
- University of Louisville (US)
- Abramson Cancer Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-05-21
- Volume
- 109
- Issue
- 23
- Pages
- 8983-8988
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3384197
- OpenAlex
- W2066808338
- Cited by
- 483
- References
- 36
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 33 · 2023: 34 · 2022: 41 · 2021: 55 · 2020: 39 · 2019: 28 · 2018: 30 · 2017: 36 · 2016: 35 · 2015: 45 · 2014: 35 · 2013: 24 · 2012: 9
- FWCI
- 11.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA057341, R21CA133688, R01CA118434, P30CA016520)
- National Center for Research Resources (P20RR018733)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- c-Myc, proline metabolism, glutamine metabolism, glutaminase, proline dehydrogenase, proline biosynthesis, pyrroline-5-carboxylate synthase, PYCR1, miR-23b, cancer metabolism, tumor cell proliferation, Burkitt lymphoma, prostate cancer, glutamate, TCA cycle
- MeSH terms
- delta-1-Pyrroline-5-Carboxylate Reductase, Carbon Isotopes, DNA-Binding Proteins, Glutamine, Humans, Gas Chromatography-Mass Spectrometry, Nitrogen Isotopes, Oxidation-Reduction, Proline, Proline Oxidase, Pyrroline Carboxylate Reductases, Transcription Factors, Blotting, Western, Gene Expression Regulation, Enzymologic, Reactive Oxygen Species, Nuclear Magnetic Resonance, Biomolecular, Reverse Transcriptase Polymerase Chain Reaction, MicroRNAs, Cell Line, Tumor, Chromatin Immunoprecipitation, Gene Knockdown Techniques, Real-Time Polymerase Chain Reaction
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