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Proline metabolism and cancer: emerging links to glutamine and collagen.

Phang JM, Liu W, Hancock CN, Fischer JW - Curr Opin Clin Nutr Metab Care (2015)

Bottom Line: The regulatory functions of proline metabolism proposed 3 decades ago have found relevance in many areas.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).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.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.

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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Related in: MedlinePlus

A proposed metabolic model involving glutamine, proline and collagen. The depicted tumor cell is also applicable to nonmalignant proliferating cells. The sources for glutamine are shown on the upper left and the source for proline is shown in the upper right. These are not necessarily specific for cellular or other anatomic sites. GSA and P5C are tautomers. Their interconversions are spontaneous. Overall, the proposed pathway is that glutamine synthesized from adequate protein intake is used for energy and de-novo synthesis of purines and pyrimidines. Proline is an important amino acid product that is used for signaling as well as an alternate source of ATP. During nutritional plenty, proline is stored in collagen, the main component of ECM. This reservoir of proline can be mobilized during conditions of nutritional stress. ECM, extracellular matrix; GSA, glutamic-γ- semialdehyde; P5C, pyrroline-5-carboxylate; ORN, ornithine; PA, polyamines; PPP, pentose phosphate pathway. The black circles designate specific enzymes numbered as follows: 1, proline dehydrogenase a.k.a. proline oxidise; 2, P5C synthase; 3, P5C reductase 1 and 2; 4, P5C reductase L; 5, glutaminase.
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Figure 1: A proposed metabolic model involving glutamine, proline and collagen. The depicted tumor cell is also applicable to nonmalignant proliferating cells. The sources for glutamine are shown on the upper left and the source for proline is shown in the upper right. These are not necessarily specific for cellular or other anatomic sites. GSA and P5C are tautomers. Their interconversions are spontaneous. Overall, the proposed pathway is that glutamine synthesized from adequate protein intake is used for energy and de-novo synthesis of purines and pyrimidines. Proline is an important amino acid product that is used for signaling as well as an alternate source of ATP. During nutritional plenty, proline is stored in collagen, the main component of ECM. This reservoir of proline can be mobilized during conditions of nutritional stress. ECM, extracellular matrix; GSA, glutamic-γ- semialdehyde; P5C, pyrroline-5-carboxylate; ORN, ornithine; PA, polyamines; PPP, pentose phosphate pathway. The black circles designate specific enzymes numbered as follows: 1, proline dehydrogenase a.k.a. proline oxidise; 2, P5C synthase; 3, P5C reductase 1 and 2; 4, P5C reductase L; 5, glutaminase.

Mentions: Of nonessential amino acids, glutamine is especially important in metabolism. It is the indispensable source of imido groups for synthesis of purines and pyrimidines. In a physiologic setting, glutamine is synthesized in muscle and transferred to gastrointestinal tract as fuel and to central organs for metabolic processing (Fig. 1)[12]. Citrulline and proline are the two main amino acid products. In tissue culture, the supraphysiologic concentrations of glutamine are combined with diabetic levels of glucose (450 mg/dl) to maximize proliferation, especially of tumor cells. Thus, it is not surprising that cultured tumor cells are ‘addicted’ to glutamine and glucose. The dysregulation in cancer cells includes an increase in glutamine transporters and increased activity of glutaminase [13]. Additionally, glutamine synthetase is downregulated by oncogenes, for example, cellular myelocytomatosis oncogene (c-MYC) [14]. Thus, high levels of glutaminase and low levels of glutamine synthetase make exogenous sources of glutamine essential.


Proline metabolism and cancer: emerging links to glutamine and collagen.

Phang JM, Liu W, Hancock CN, Fischer JW - Curr Opin Clin Nutr Metab Care (2015)

A proposed metabolic model involving glutamine, proline and collagen. The depicted tumor cell is also applicable to nonmalignant proliferating cells. The sources for glutamine are shown on the upper left and the source for proline is shown in the upper right. These are not necessarily specific for cellular or other anatomic sites. GSA and P5C are tautomers. Their interconversions are spontaneous. Overall, the proposed pathway is that glutamine synthesized from adequate protein intake is used for energy and de-novo synthesis of purines and pyrimidines. Proline is an important amino acid product that is used for signaling as well as an alternate source of ATP. During nutritional plenty, proline is stored in collagen, the main component of ECM. This reservoir of proline can be mobilized during conditions of nutritional stress. ECM, extracellular matrix; GSA, glutamic-γ- semialdehyde; P5C, pyrroline-5-carboxylate; ORN, ornithine; PA, polyamines; PPP, pentose phosphate pathway. The black circles designate specific enzymes numbered as follows: 1, proline dehydrogenase a.k.a. proline oxidise; 2, P5C synthase; 3, P5C reductase 1 and 2; 4, P5C reductase L; 5, glutaminase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255759&req=5

Figure 1: A proposed metabolic model involving glutamine, proline and collagen. The depicted tumor cell is also applicable to nonmalignant proliferating cells. The sources for glutamine are shown on the upper left and the source for proline is shown in the upper right. These are not necessarily specific for cellular or other anatomic sites. GSA and P5C are tautomers. Their interconversions are spontaneous. Overall, the proposed pathway is that glutamine synthesized from adequate protein intake is used for energy and de-novo synthesis of purines and pyrimidines. Proline is an important amino acid product that is used for signaling as well as an alternate source of ATP. During nutritional plenty, proline is stored in collagen, the main component of ECM. This reservoir of proline can be mobilized during conditions of nutritional stress. ECM, extracellular matrix; GSA, glutamic-γ- semialdehyde; P5C, pyrroline-5-carboxylate; ORN, ornithine; PA, polyamines; PPP, pentose phosphate pathway. The black circles designate specific enzymes numbered as follows: 1, proline dehydrogenase a.k.a. proline oxidise; 2, P5C synthase; 3, P5C reductase 1 and 2; 4, P5C reductase L; 5, glutaminase.
Mentions: Of nonessential amino acids, glutamine is especially important in metabolism. It is the indispensable source of imido groups for synthesis of purines and pyrimidines. In a physiologic setting, glutamine is synthesized in muscle and transferred to gastrointestinal tract as fuel and to central organs for metabolic processing (Fig. 1)[12]. Citrulline and proline are the two main amino acid products. In tissue culture, the supraphysiologic concentrations of glutamine are combined with diabetic levels of glucose (450 mg/dl) to maximize proliferation, especially of tumor cells. Thus, it is not surprising that cultured tumor cells are ‘addicted’ to glutamine and glucose. The dysregulation in cancer cells includes an increase in glutamine transporters and increased activity of glutaminase [13]. Additionally, glutamine synthetase is downregulated by oncogenes, for example, cellular myelocytomatosis oncogene (c-MYC) [14]. Thus, high levels of glutaminase and low levels of glutamine synthetase make exogenous sources of glutamine essential.

Bottom Line: The regulatory functions of proline metabolism proposed 3 decades ago have found relevance in many areas.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).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.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.

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.

Show MeSH
Related in: MedlinePlus