title: Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides.
abstract: The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockade of PB decreases tumor cell growth and energy production. Addition of Δ(1)-pyrroline-5-carboxylate (P5C) or proline reverses the effects of P5C synthase knockdown but not P5C reductases knockdown. Importantly, the reversal effect of proline was blocked by concomitant proline dehydrogenase/oxidase (PRODH/POX) knockdown. These findings suggest that the important regulatory contribution of PB to tumor growth derives from metabolic cycling between proline and P5C rather than product proline or intermediate P5C. We further document the critical role of PB in maintaining pyridine nucleotide levels by connecting the proline cycle to glycolysis and to the oxidative arm of the pentose phosphate pathway. These findings establish a novel function of PB in tumorigenesis, linking the reprogramming of glucose, glutamine and pyridine nucleotides, and may provide a novel target for antitumor therapy.
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Chad N
authors.initials: CN
authors.lastname: Hancock
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Fischer
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Harman
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
mesh_terms: D000332:Aerobiosis; D017209:Apoptosis; D053898:Biosynthetic Pathways; D002453:Cell Cycle; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D061986:MCF-7 Cells; D009711:Nucleotides / Q000378:metabolism*; D009952:Ornithine / Q000378:metabolism; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway; D011392:Proline / Q000096:biosynthesis*; D011725:Pyridines / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D009711:Nucleotides; D011725:Pyridines; D005973:Glutamine; D011392:Proline; D009952:Ornithine