title: Proline metabolism and cancer: emerging links to glutamine and collagen.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Chad N
authors.initials: CN
authors.lastname: Hancock
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D011392:Proline / Q000378:metabolism*; D000090063:Proto-Oncogene Mas
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D005973:Glutamine; D003094:Collagen; D011392:Proline