Journal
ANNUAL REVIEW OF NUTRITION, VOL 30
Volume 30, Issue -, Pages 441-463Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev.nutr.012809.104638
Keywords
cancer; collagen; bioenergetics; tumor suppressor; microRNA; oxLDL
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Funding
- Intramural NIH HHS [Z01 BC010743, ZIA BC010744, ZIA BC010743] Funding Source: Medline
- PHS HHS [HHSN27612080001] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [ZIABC010746, ZIABC010744, ZIABC010743] Funding Source: NIH RePORTER
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Proline, the only proteinogenic secondary amino acid, is metabolized by its own family of enzymes responding to metabolic stress and participating in metabolic signaling. Collagen in extracellular matrix, connective tissue, and bone is an abundant reservoir for prolific. Matrix metalloproteinases degrading collagen are activated during stress to make proline available, and proline oxidase, the first enzyme in proline degradation, is induced by p53, peroxisome proliferator-activated receptor gamma (PPAR gamma) and its ligands, and by AMP-activated protein kinase downregulating mTOR. Metabolism of prolific generates electrons to produce ROS and initiates a variety of downstream effects, including blockade of the cell cycle, autophagy, and apoptosis. The electrons can also enter the electron transport chain to produce adenosine triphosphate for survival under nutrient stress. Pyrroline-5-carboxylate, the product of prolific oxidation, is recycled back to proline with redox transfers or is sequentially converted to glutamate and alpha-ketoglutarate. The latter augments the prolyl hydroxylation of hypoxia-inducible factor-1 alpha and its proteasomal degradation. These effects of proline oxidase, as well as its decreased levels in tumors, support its role as a tumor suppressor. The mechanism for its decrease is mediated by a specific microRNA. The metabolic signaling by prolific oxidase between oxidized low-density lipoproteins and autophagy provides a functional link between obesity and increased cancer risk.
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