Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides

Liu, Wei; Hancock, Chad N.; Fischer, Joseph W.; Harman, Meredith; Phang, James M.

doi:10.1038/srep17206

Cited by 138 publications

(173 citation statements)

References 34 publications

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“…The interconversion is known as a “proline cycle” (conversion of proline-P5C in mitochondria by PRODH/POX and P5C-proline in cytosol by P5C-reductase) that transfers reducing and oxidizing potential between mitochondria and cytosol using NAPDH/NADP + [23, 24]. This shuttle is coupled to glycolisys and pentose phosphate pathway that supports biosynthesis of pyridine nucleotides [10] . Therefore, down-regulation of PRODH/POX may affect DNA biosynthesis and cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the role of specific metabolites of proline interconversion in the mechanism that leads to apoptosis or autophagy remains unknown. Large amount of proline is also derived from glutamine that is linked to the tumor metabolism [10, 12, 50, 51]. Therefore, the identification of specific pathway of proline metabolism that is involved in regulation of apoptosis/survival is of particular importance and requires further studies.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms that utilize proline are collagen biosynthesis and proline conversion into pyrroline-5-carboxylic acid (P5C) [4, 8-10]. The second process is catalyzed by mitochondrial proline dehydrogenase/proline oxidase (PRODH/POX).…”

Section: Introductionmentioning

confidence: 99%

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Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

Zaręba

Surażyński

Chruściel

et al. 2017

Cell Physiol Biochem

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Background/Aims: The effect of impaired intracellular proline availability for proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis was studied. Methods: We generated a constitutively knocked-down PRODH/POX MCF-7 breast cancer cell line (MCF-7^shPRODH/POX) as a model to analyze the functional consequences of impaired intracellular proline levels. We have used inhibitor of proline utilization in collagen biosynthesis, 2-metoxyestradiol (MOE), inhibitor of prolidase that generate proline, rapamycin (Rap) and glycyl-proline (GlyPro), substrate for prolidase. Collagen and DNA biosynthesis were evaluated by radiometric assays. Cell viability was determined using Nucleo-Counter NC-3000. The activity of prolidase was determined by colorimetric assay. Expression of proteins was assessed by Western blot and immunofluorescence bioimaging. Concentration of proline was analyzed by liquid chromatography with mass spectrometry. Results: PRODH/POX knockdown decreased DNA and collagen biosynthesis, whereas increased prolidase activity and intracellular proline level in MCF-7^shPRODH/POX cells. All studied compounds decreased cell viability in MCF-7 and MCF-7^shPRODH/POX cells. DNA biosynthesis was similarly inhibited by Rap and MOE in both cell lines, but GlyPro inhibited the process only in MCF-7^shPRODH/POX and MOE+GlyPro only in MCF-7 cells. All the compounds inhibited collagen biosynthesis, increased prolidase activity and cytoplasmic proline level in MCF-7^shPRODH/POX cells and contributed to the induction of pro-survival mode only in MCF-7^shPRODH/POX cells. In contrast, all studied compounds upregulated expression of pro-apoptotic protein only in MCF-7 cells. Conclusion: PRODH/POX was confirmed as a driver of apoptosis and proved the eligibility of MCF-7^shPRODH/POX cell line as a highly effective model to elucidate the different mechanisms underlying proline utilization or generation in PRODH/POX-dependent pro-apoptotic pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

Zaręba

Surażyński

Chruściel

et al. 2017

Cell Physiol Biochem

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“…2). Proline synthesis from glutamine is upregulated by oncogenic signalling to promote proliferation of lymphoma cells, and this amino acid is synthesized even when provided exogenously (42). Of note, proline synthesis is unique in that it directly requires two molecules of NAD(P)H for reduction, linking its synthesis to NAD + regeneration or NADPH consumption (43).…”

Section: Amino Acidsmentioning

confidence: 99%

“…Of note, proline synthesis is unique in that it directly requires two molecules of NAD(P)H for reduction, linking its synthesis to NAD + regeneration or NADPH consumption (43). Proline synthesis has been argued to consume NADPH to drive pentose phosphate pathway activity (13,42), but loss of this activity is expected to impair proline synthesis only in cases where other NADPH-producing pathways cannot compensate (44). …”

Section: Amino Acidsmentioning

confidence: 99%

The redox requirements of proliferating mammalian cells

Hosios

Heiden

2018

Journal of Biological Chemistry

117

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Cell growth and division requires nutrients, and proliferating cells use a variety of sources to acquire the amino acids, lipids, and nucleotides that support macromolecule synthesis. Lipids are more reduced than other nutrients, whereas nucleotides and amino acids are typically more oxidized. Cells must therefore generate reducing and oxidizing (redox) equivalents to convert consumed nutrients into biosynthetic precursors. To that end, redox cofactor metabolism plays a central role in meeting cellular redox requirements. In this review, we highlight the biosynthetic pathways that involve redox reactions and discuss their integration with metabolism in proliferating mammalian cells.

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How signaling pathways link extracellular mechano‐environment to proline biosynthesis: A hypothesis

Chen

Guo

2021

BioEssays

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We propose a signaling pathway in which cell-extracellular matrix (ECM) adhesion components PINCH-1 and kindlin-2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH-1 expression via integrin signaling, which suppresses dynamin-related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin-2 translocation into mitochondria and interaction with Δ 1 -pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1). Kindlin-2 interaction with PYCR1 protects the latter from proteolytic degradation, leading to elevated PYCR1 level. Additionally, PINCH-1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. K E Y W O R D Scancer, collagen, extracellular mechano-environment, fibrosis, focal adhesion proteins, mitochondrial dynamics, proline biosynthesis OMM, outer mitochondrial membrane; P5C, Δ 1 -pyrroline-5-carboxylate; P5CS, Δ 1 -pyrroline-5-carboxylate synthase; PH, pleckstrin homology; PYCR, Δ 1 -pyrroline-5-carboxylate reductase; ROS, reactive oxygen species; TCA, tricarboxylic acid; TGF, transforming growth factor as an electron donor. Proline biosynthesis are influenced by both the availability of the substrate (i.e. P5C) and the expression levels and activities of the enzyme (i.e. PYCR). Three isoforms of PYCR, namely PYCR1, 2, and L, have been identified in mammals. [1,4] PYCR1 and 2 share a high level (approximately 84%) of similarity in amino acid sequence, whereas the similarity in amino acid sequence between PYCRL and PYCR1/2 is considerably lower (approximately 45%).All three PYCRs are encoded by genes (i.e. PYCR1, 2, and L) in the nuclei. However, after PYCR1 and 2 proteins are synthesized, they are transported from the cytosol into mitochondria where they catalyze the final step in proline biosynthesis (i.e. conversion of P5C to proline).

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Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides

Cited by 138 publications

References 34 publications

Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

The redox requirements of proliferating mammalian cells

How signaling pathways link extracellular mechano‐environment to proline biosynthesis: A hypothesis

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