Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

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...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2012-06, Vol.109 (23), p.8983-8988
Main Authors:	Liu, Wei, Le, Anne, Hancock, Chad, Lane, Andrew N., Dang, Chi V., Fan, Teresa W.-M., Phang, James M.
Format:	Article
Language:	eng
Subjects:	Apoptosis Biological Sciences Biosynthesis Blotting, Western Cancer Carbon Isotopes - metabolism Catabolism Cell growth Cell Line, Tumor Cellular metabolism Chromatin Immunoprecipitation delta-1-Pyrroline-5-Carboxylate Reductase DNA-Binding Proteins - metabolism Energy metabolism Gas Chromatography-Mass Spectrometry Gene Expression Regulation, Enzymologic - genetics Gene Expression Regulation, Enzymologic - physiology Gene Knockdown Techniques Glutamine - metabolism Humans Metabolism MicroRNAs - metabolism Nitrogen Isotopes - metabolism Nuclear Magnetic Resonance, Biomolecular Oxidation-Reduction Proline - metabolism Proline Oxidase - metabolism Prostate cancer Pyrroline Carboxylate Reductases - metabolism Reactive Oxygen Species - metabolism Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Small interfering RNA T lymphocytes Transcription Factors - metabolism Tumors
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Summary:	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 wellrecognized, glutamate can also be converted to proline through ∆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 upregulating 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. MYCinduced 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.
ISSN:	0027-8424 1091-6490