Stable isotope resolved metabolomics of lung cancer in a SCID mouse model

Fan, Teresa W.‐M.; Lane, Andrew N.; Higashi, Richard M.; Yan, Jun

doi:10.1007/s11306-010-0249-0

Cited by 97 publications

(182 citation statements)

References 44 publications

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“…Transformed cells from different origins typically up-regulate both glucose and glutamine consumption as sources of metabolic energy and as precursors for biosynthesis of macromolecules (13,27). The MYC oncogene, which plays a critical role in many human cancers, is considered a master regulator of cell metabolism and proliferation.…”

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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411

401

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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.

Self Cite

411

401

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“…To detect plasma level of 13 C 18 -OA, mice were given 13 C 18 -OA as above and blood was collected from tail snip either before (0h), or 1, 2 and 3h after gavage. Lipid was extracted from proximal intestines and plasma 42 and 13 C 18 -OA levels were determined by direct infusion nanospray FT-MS (Orbitrap Fusion ™ Tribrid ™ Mass Spectrometer, Thermo Scientific, Waltham, MA) using a modification of a previous method 43 . Briefly, aliquots of the lipid extracts were diluted twenty-fold in isopropanol:chloroform:methanol (4:2:1), introduced into the TriVersa NanoMate® (Advion, Inc., Ithaca, NY) and analyzed on the Orbitrap Fusion in negative ion mode to estimate the appropriate amount of d34-OA to spike.…”

Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

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237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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“…13 C abundance of labeled metabolites was calculated from the ratio of the peak areas of the satellite peaks to the total peak intensity according to the equation F=I 13C_satellites /I 13C_satellites +I 12C_central peak , where I is the peak area. 29, 30 We observed that the satellite at 5.36 ppm was often difficult to deconvolve because of partial overlap with the allantoin peak; its integral value was, therefore, obtained from the symmetric satellite peak at 5.08 ppm. Breathing and body temperature were monitored during MRI (SA Instruments, Inc., Stony Brook, NY) and maintained around 30 breaths per minute and 37°C, respectively.…”

Section: Dc/floxmentioning

confidence: 99%

2-Deoxy-d-Glucose Ameliorates PKD Progression

Chiaravalli¹,

Rowe²,

Mannella³

et al. 2015

JASN

152

120

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Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-D-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of 13 C-glucose and conversion to 13 C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMPactivated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.

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Stable isotope resolved metabolomics of lung cancer in a SCID mouse model

Cited by 97 publications

References 44 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

An obligatory role for neurotensin in high-fat-diet-induced obesity

2-Deoxy-d-Glucose Ameliorates PKD Progression

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