{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:35:46Z","timestamp":1791419746599,"version":"4.3.3"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,6,5]]},"abstract":"<jats:p>\n                    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 \u0394\n                    <jats:sup>1<\/jats:sup>\n                    -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\n                    <jats:sup>13<\/jats:sup>\n                    C,\n                    <jats:sup>15<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1203244109","type":"journal-article","created":{"date-parts":[[2012,5,21]],"date-time":"2012-05-21T23:03:58Z","timestamp":1337641438000},"page":"8983-8988","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":436,"title":["Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC"],"prefix":"10.1073","volume":"109","author":[{"given":"Wei","family":"Liu","sequence":"first","affiliation":[{"name":"Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Hancock","sequence":"additional","affiliation":[{"name":"Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Lane","sequence":"additional","affiliation":[{"name":"Departments of cMedicine and fChemistry, Center for Regulatory Environmental Analytical Metabolomics and"},{"name":"James Graham Brown Cancer Center, University of Louisville, KY 40202; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi V.","family":"Dang","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa W.-M.","family":"Fan","sequence":"additional","affiliation":[{"name":"Departments of cMedicine and fChemistry, Center for Regulatory Environmental Analytical Metabolomics and"},{"name":"James Graham Brown Cancer Center, University of Louisville, KY 40202; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Phang","sequence":"additional","affiliation":[{"name":"Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,5,21]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.05.005"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3556"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002459107"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.1.1"},{"key":"e_1_3_3_6_2","first-page":"1810","article-title":"Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species","volume":"61","author":"Donald SP","year":"2001","unstructured":"SP Donald, et al., Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species. 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