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      Proline metabolism and cancer: emerging links to glutamine and collagen

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          Abstract

          Purpose of review

          Proline metabolism impacts a number of regulatory targets in both animals and plants and is especially important in cancer. Glutamine, a related amino acid, is considered second in importance only to glucose as a substrate for tumors. But proline and glutamine are interconvertible and linked in their metabolism. In animals, proline and glutamine have specific regulatory functions and their respective physiologic sources. A comparison of the metabolism of proline and glutamine would help us understand the importance of these two nonessential amino acids in cancer metabolism.

          Recent findings

          The regulatory functions of proline metabolism proposed 3 decades ago have found relevance in many areas. For cancer, these functions play a role in apoptosis, autophagy and in response to nutrient and oxygen deprivation. Importantly, proline-derived reactive oxygen species served as a driving signal for reprogramming. This model has been applied by others to metabolic regulation for the insulin-prosurvival axis, induction of adipose triglyceride lipase for lipid metabolism and regulation of embryonic stem cell development. Of special interest, modulatory proteins such as parkinson protein 7 and oral cancer overexpressed 1 interact with pyrroline-5-carboxylate reductase, a critical component of the proline regulatory axis. Although the interconvertibility of proline and glutamine has been long established, recent findings showed that the proto-oncogene, cellular myelocytomatosis oncogene, upregulates glutamine utilization (glutaminase) and routes glutamate to proline biosynthesis (pyrroline-5-carboxylate synthase, pyrroline-5-carboxylate reductases). Additionally, collagen, which contains large amounts of proline, may be metabolized to serve as a reservoir for proline. This metabolic relationship as well as the new regulatory targets of proline metabolism invites an elucidation of the differential effects of these nonessential amino acids and their production, storage and mobilization.

          Summary

          Mechanisms by which the proline regulatory axis modulates the cancer phenotype are being revealed. Proline can be synthesized from glutamine as well as derived from collagen degradation. The metabolism of proline serves as a source of energy during stress, provides signaling reactive oxygen species for epigenetic reprogramming and regulates redox homeostasis.

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          Most cited references22

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          Cancer genes and the pathways they control.

          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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            Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells.

            Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Staying alive: metabolic adaptations to quiescence.

              Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. In some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the PI3Kinase/TOR signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOR kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. In this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems.
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                Author and article information

                Journal
                Curr Opin Clin Nutr Metab Care
                Curr Opin Clin Nutr Metab Care
                COCNM
                Current Opinion in Clinical Nutrition and Metabolic Care
                Lippincott Williams & Wilkins
                1363-1950
                1473-6519
                January 2015
                04 December 2014
                : 18
                : 1
                : 71-77
                Affiliations
                Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA
                Author notes
                Correspondence to James M. Phang, MD, Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA. Tel: +1 301 846 5367; fax: +1 301 846 6093; e-mail phangj@ 123456mail.nih.gov
                Article
                00012
                10.1097/MCO.0000000000000121
                4255759
                25474014
                55f5c3f9-16a3-409d-9d5a-26191a96ba22
                © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0

                History
                Categories
                PROTEIN, AMINO ACID METABOLISM AND THERAPY: Edited by Olav Rooyackers and Sidney M. Morris Jr.
                Custom metadata
                TRUE

                apoptosis,autophagy,collagen,glutamine,metabolic stress
                apoptosis, autophagy, collagen, glutamine, metabolic stress

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