Stimulation of the hexosemonophosphate‐pentose pathway by pyrroline‐5‐carboxylate in cultured cells

Phang, James M.; Downing, Sylvia J.; Yeh, Grace Chao; Smith, Robert J.; Williams, Jeffery A.; Hagedorn, Curt H.

doi:10.1002/jcp.1041100306

Cited by 53 publications

(23 citation statements)

References 28 publications

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“…The metabolic advantage afforded by the increased conversion of glutamine to proline remains unclear, but the conversion of one nonessential amino acid to another for protein synthesis seems unlikely. The previously described metabolic interlock between proline synthesis and pentose phosphate pathway offers an attractive model for understanding the up-regulation of the proline synthetic pathway by MYC (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

Liu

Hancock

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS). Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less wellrecognized, glutamate can also be converted to proline through Δ 1 -pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b* mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b* is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS. Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through upregulating miR-23b*. The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects. Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYCinduced proline biosynthesis from glutamine was directly confirmed using 13 C, 15 N-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism. Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies.amino acids | redox signaling | reactive oxygen species | miRNA | metabolic tumor suppressor

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Section: Discussionmentioning

confidence: 99%

Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

Liu

Hancock

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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405

401

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“…Although the current study emphasizes ROS/superoxides, the generation of P5C by POX also may be an important metabolic consequence of POX induction. The exposure of cells to exogenous P5C has marked consequences on glucose metabolism in cultured mammalian cells (Phang et al, 1982). In plants and yeast, P5C has been shown to be cytotoxic and may play a role in cell death.…”

Section: Discussionmentioning

confidence: 99%

Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling

et al. 2006

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Proline oxidase (POX), often considered a 'housekeeping enzyme' might play an important role in apoptosis. We have shown that POX generated proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, and induced apoptosis through the mitochondrial (intrinsic) pathway. In our current report, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter and found POX-stimulated expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), DR5 and cleavage of caspase-8. Importantly, apoptosis measured by flow cytometry was partially inhibited by Z-IETD-FMK, a specific inhibitor of caspase-8. These findings suggest that the extrinsic (death receptor) pathway also is activated by POX. Furthermore, the mechanism of this effect on the extrinsic pathway, specifically, the induction of TRAIL by POX, may be mediated by NFAT transcription factors. Additionally, POX expression also dramatically decreased phosphorylation of MEK and ERK, and the decrease was partially reversed by expression of manganese superoxide dismutase (MnSOD). Overexpression of constitutively active form of MEK, acMEK, partially blocked POX-induced apoptosis. These findings suggest the involvement of MEK/ERK signaling and further confirm the role of ROS/superoxides in POXinduced apoptosis. Combined with previously published data, we conclude that POX may induce apoptosis through both intrinsic and extrinsic pathways and is involved in nuclear factor of activated T cells (NFAT) signaling and regulation of the MEK/ERK pathway. It is suggested that, as a nutrition factor, POX may modulate apoptosis signals induced by p53 or other anti-cancer agents and enhance apoptosis in stress situations.

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“…LLC-PIC, and LLC-RIC, cells have the character of proximal tubule cells. 1,12 T h e culture medium for these cells was minimum essential medium (MEM) supplemented with 10% fetal calf serum (FCS). BALBic 3T3 (mouse) fibroblasts were given by Professor A. Ichihara (Enzyme Research Center, Tokushima, Japan).…”

Section: Partial Purification Of Tucgfmentioning

confidence: 99%

Activity of Keratinocyte Growth Factor‐Like Substance Extracted from Rabbit Liver on Renal Tubular Cell Growth during Compensatory Renal Hyperplasia

et al. 1997

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Background:In response to unilateral nephrectomy, the rabbit liver transiently produces 2 growth regulators for cultured renal cortical tubular cells: a tubular cell growth factor and a growth inhibitor. We report on the effects of the tubular cell growth factor on a variety of cell lines. Methods: The tubular cell growth factor activity was partially purified from the rabbit liver by using gel filtration and ion-exchange chromatography. The activity was monitored by the incorporation of iododeoxyuridine into DNA of cultured cells. Expression of the fibroblast growth factor receptor-2 in the rabbit kidney was determined by the immunoblot analysis.Results: This growth factor stimulated the DNA synthesis in LLC-PK, cells, LLC-RK, cells, and human keratinocytes. It did not affect the growth of BS-C-1 cells, MDCK cells, BALB/c 3T3 fibroblasts, or rat parenchymal hepatocytes. The additive effect of this factor on the DNA synthesis of cultured tubular cells maximally was stimulated by insulin-like growth factor-I, basic fibroblast growth factor, and epidermal growth factor, but was not stimulated by keratinocyte growth factor. The amount of this activity also increased in the liver after sham operation. In the days after surgery, expression of fibroblast growth factor receptor-?, which includes the keratinocyte growth factor receptor, was down-regulated in the kidneys of both uninephrectomized and sham-operated rabbits. Conclusion: These findings indicate that tubular cell growth factor in the liver seems to be a keratinocyte growth factor, and acts in an endocrine manner in renal tubular hyperplasia.

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Stimulation of the hexosemonophosphate‐pentose pathway by pyrroline‐5‐carboxylate in cultured cells

Cited by 53 publications

References 28 publications

Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling

Activity of Keratinocyte Growth Factor‐Like Substance Extracted from Rabbit Liver on Renal Tubular Cell Growth during Compensatory Renal Hyperplasia

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