High-fructose corn syrup enhances intestinal tumor growth in mice

Goncalves, Marcus D.; Lu, Changyuan; Tutnauer, Jordan; Hartman, Travis; Hwang, Seo Kyoung; Murphy, Charles J.; Pauli, Chantal; Morris, Roxanne; Taylor, Samuel; Bosch, Kaitlyn; Yang, Suk–Jin; Wang, Yumei; Riper, Justin Van; Lekaye, H. Carl; Roper, Jatin; Kim, Young; Chen, Qiuying; Gross, Steven S.; Rhee, Kyu Y.; Cantley, Lewis C.; Yun, Jang−Gn

doi:10.1126/science.aat8515

Cited by 267 publications

(218 citation statements)

References 52 publications

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“…Fructose is also implicated in cancer development. Feeding mice with high-fructose corn syrup enhances tumor growth independently of obesity and metabolic syndrome (Goncalves et al, 2019). Interestingly, expression levels of the polyol pathway enzyme AR correlate with the epithelial-to-mesenchymal transition (EMT) status in cancer cell lines as well as in cancers in patients.…”

Section: Discussionmentioning

confidence: 99%

The polyol pathway is a crucial glucose sensor inDrosophila

Sano

Nakamura

Yamane

et al. 2020

Preprint

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SummaryA major nutrient source for animals is glucose, which induces transcriptional responses that shift metabolism. Such metabolic adaptation should be appropriately scaled to the ingested glucose levels, and decoupling causes human metabolic diseases. However, the identity of the crucial sensor metabolite(s) that transmit circulating glucose levels to the transcriptional machinery remains elusive. Here we show that the polyol pathway, which converts glucose to fructose via sorbitol, is required for activation of the master metabolic regulator Mondo, the Drosophila homologue of MondoA/ChREBP. We demonstrate that under normal nutritional conditions polyol pathway metabolites promote Mondo’s nuclear localization and cause global changes in metabolic gene expression. Polyol pathway mutants block nuclear localization of Mondo and Mondo-mediated gene expression despite intact glycolytic and pentose phosphate pathways. Our results uncover the normal physiological function of this pathway and cast a new light on the adverse effects of high fructose diets in human health.

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Section: Discussionmentioning

confidence: 99%

The polyol pathway is a crucial glucose sensor inDrosophila

Sano

Nakamura

Yamane

et al. 2020

Preprint

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“…Tumors can also metabolize fructose. This has been shown for a variety of tumor 46 types arising from the breast, brain, prostate, ovary, pancreas, intestine, lung, liver, kidney, and blood ( (5,12), Breast: (13,14) Brain: (15,16), Prostate: (17), Ovary: Jin et al, 2019, Pancreas: (19,20), Intestine: (21), Lung: (22)(23)(24), Liver: (25), Kidney: (26), Blood:…”

Section: Introductionmentioning

confidence: 88%

GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase

Liang

Taylor

Nahiyaan

et al. 2020

Preprint

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Background: Fructose is an abundant source of carbon and energy for cells to use for metabolism, but only certain cell types use fructose to proliferate. Tumor cells that can metabolize fructose have a fitness advantage over their neighboring cells, but the proteins that mediate fructose metabolism in this context are unknown. Here, we investigated the determinants of fructose-mediated cell proliferation.Methods: We quantified the ability of 14 cell lines to proliferate in fructose-containing media (i.e. the fructolytic ability) using live cell imaging and crystal violet assays. The expression and abundance of proteins related to fructose metabolism were assessed using RT-qPCR and western blot, respectively, for each cell line. Using a positive selection approach, we “trained” the non-fructolytic PC3 cell line to utilize fructose for proliferation. RNA-seq was then performed to identify key transcriptional changes associated with fructolytic ability. We overexpressed and deleted proteins associated with fructose metabolism, and performed metabolic profiling using the Seahorse Bioanalyzer and LC/MS-based metabolomics.Results: We found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine a cell’s fructolytic ability. Cells cultured chronically in fructose can develop fructolytic ability if SLC2A5, encoding the fructose transporter, GLUT5, gets upregulated. Overexpression of GLUT5 in non-fructolytic cells enables growth in fructose-containing media across cells of different origins. GLUT5 permitted fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase (KHK).Conclusions: We show that GLUT5 is a robust and generalizable driver of fructose-dependent cell proliferation. This indicates that fructose uptake is a limiting factor for fructose-mediated cell proliferation. We further demonstrate that cancer cell proliferation with fructose is independent of KHK.

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“…Pellets were stored at −20°C until analysis. For analysis pellets were suspended in 45 μl mobile phase A of which 10 μl was analyzed by ion-pairing LC/MS as described 12 .…”

Section: Methodsmentioning

confidence: 99%

“…Here we tested if release of ATP also underlies most of the PPi found in the extracellular milieu of ANKH-containing cells. Moreover, we applied global metabolite profiling 12 on medium of HEK293-ANKH cells to gain a comprehensive overview of metabolites extruded by cells in an ANKH-dependent manner. Our results provide new and unexpected insights into the substrate spectrum and anti-mineralization properties of ANKH and also show that ANKH has functions beyond inhibition of inhibition of pathological mineralization as it is, for instance, essential for normal bone development.…”

Section: Introductionmentioning

confidence: 99%

Ankylosis homologue (ANKH) controls extracellular citrate and pyrophosphate homeostasis and affects bone mechanical performance

Szeri

Lundkvist

Donnelly

et al. 2019

Preprint

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28 29 30 31 Keywords: 32 extracellular citrate, extracellular pyrophosphate, ATP release, ANKH/ANK, ectopic 33 mineralization, bone 34 35 36 37 2 Abstract 38 The membrane protein Ankylosis homologue (ANKH, mouse orthologue: ANK) prevents 39 mineralization of joint-space and articular cartilage. The accepted view is that ANKH mediates 40 cellular release of inorganic pyrophosphate (PPi), a strong physiological inhibitor of 41 mineralization. Using global metabolite profiling, we identified citrate as the most prominent 42 metabolite leaving HEK293 cells in an ANKH-dependent manner. Although PPi levels were 43 increased in culture medium of HEK293-ANKH cells, PPi was formed extracellularly after release 44 of ATP and other nucleoside triphosphates. Ank ank/ank mice, which lack functional ANK, had 45 substantially reduced concentrations of citrate in plasma and urine, while citrate was undetectable 46 in urine of a human patient lacking functional ANKH. Bone hydroxyapatite of Ank ank/ank mice also 47 contained markedly reduced levels of citrate and PPi and displayed diminished strength. 48Together, our data show that ANKH is a crucial factor in extracellular citrate and PPi homeostasis 49 that is essential for normal bone development.

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High-fructose corn syrup enhances intestinal tumor growth in mice

Cited by 267 publications

References 52 publications

The polyol pathway is a crucial glucose sensor inDrosophila

The polyol pathway is a crucial glucose sensor inDrosophila

GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase

Ankylosis homologue (ANKH) controls extracellular citrate and pyrophosphate homeostasis and affects bone mechanical performance

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