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The metabolism of proline, a stress substrate, modulates carcinogenic pathways
Open accessAbstract
The resurgence of interest in tumor metabolism has led investigators to emphasize the metabolism of proline as a "stress substrate" and to suggest this pathway as a potential anti-tumor target. Proline oxidase, a.k.a. proline dehydrogenase (POX/PRODH), catalyzes the first step in proline degradation and uses proline to generate ATP for survival or reactive oxygen species for programmed cell death. POX/PRODH is induced by p53 under genotoxic stress and initiates apoptosis by both mitochondrial and death receptor pathways. Furthermore, POX/PRODH is induced by PPARgamma and its pharmacologic ligands, the thiazolidinediones. The anti-tumor effects of PPARgamma may be critically dependent on POX/PRODH. In addition, it is upregulated by nutrient stress through the mTOR pathway to maintain ATP levels. We propose that proline is made available as a stress substrate by the degradation of collagen in the microenvironmental extracellular matrix by matrix metalloproteinases. In a manner analogous to autophagy, this proline-dependent process for bioenergetics from collagen in extracellular matrix can be designated "ecophagy".
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“In addition to its effects on glutamine metabolism, c-myc-orchestrated remodeling of non-essential amino acid metabolism involves the metabolism of proline (Phang et al., 2008).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Phang et al., 2008
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Metadata
- Authors
- Phang, J. M., Donald, S. P., Pandhare, J., & Liu, Y.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Science Applications International Corporation (United States) (US)
- Corresponding author
- Phang, James M.
- Venue
- Amino Acids
- Published
- 2008-04-10
- Volume
- 35
- Issue
- 4
- Pages
- 681-690
- ISSN
- 0939-4451 (ISSN-L)
- 1438-2199
- OpenAlex
- W1986586503
- Cited by
- 252
- References
- 60
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 8 · 2023: 13 · 2022: 15 · 2021: 20 · 2020: 12 · 2019: 15 · 2018: 15 · 2017: 18 · 2016: 10 · 2015: 15 · 2014: 15 · 2013: 13 · 2012: 11
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- public-domain
- www.springer.com/tdm (tdm)
- Locations
- Amino Acids (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
- Funders
- National Institutes of Health (n01co12400-79-0-22)
- National Cancer Institute (N01CO12400)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- proline metabolism, proline oxidase, proline dehydrogenase, cancer metabolism, p53, apoptosis, PPARγ, thiazolidinediones, mTOR, nutritional stress, collagen degradation, matrix metalloproteinases, extracellular matrix, reactive oxygen species, carcinogenesis
- MeSH terms
- Adenosine Triphosphate, Autophagy, Catalysis, Ligands, Models, Biological, Neoplasms, Proline, Proline Oxidase, Protein Kinases, Gene Expression Regulation, Enzymologic, Tumor Suppressor Protein p53, Apoptosis, Thiazolidinediones, PPAR delta, TOR Serine-Threonine Kinases
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