GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling

Chen, Wen-Lian; Jin, Xing; Wang, Mingsong; Liú, Dan; Luo, Qin; Tian, Hechuan; Cai, Lili; Meng, Lifei; Bi, Rui; Wang, Lei; Xie, Xiao Song; Yu, Guanzhen; Li, Lihui; Dong, Changsheng; Cai, Qiliang; Jia, Weiping; Wei, Wenyi; Jia, Lijun

doi:10.1172/jci.insight.131596

Cited by 75 publications

(45 citation statements)

References 59 publications

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“…We previously reported that cancer cells such as acute myeloid leukemia cells exhibited enhanced fructose utilization under low glucose conditions and that pharmacologic 1blockade of fructose utilization suppressed AML cell proliferation and enhanced the therapeutic efficacy of Ara-C 3 . Our recent findings, along with reports from other groups 2–4 , suggest that fructose is a preferred carbon source for cancer cells. As a result, high expression of the fructose transporter SLC2A5/GLUT5 was found in multiple types of cancers, enabling the increased uptake of fructose from the environment and enhancement of cancer growth and development.…”

supporting

confidence: 80%

“…Metabolites were extracted by adding 0.5 mL of 50% MeOH (−20°C), followed by homogenization for 3 min using a Bullet Blender Tissue Homogenizer (Next Advance, Inc., Averill Park, NY) and centrifugation at 13, 500 g for 10 min at 4°C. Derivatization was performed according to the method of Han et al 19 with minor modifications. 50 μL of supernatant or standard was transferred to a 1.5 mL tube and mixed with 10 μL of 200 mM 3-NPH solution, and 10 μL of the mixed 96 mM of EDC/pyridine methanolic solution.…”

Section: Methodsmentioning

confidence: 99%

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Fructose Metabolism Contributes to the Warburg effect

Han

Wang

Zhang

et al. 2020

Preprint

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SUMMARYFructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, dietary fructose rarely enters the bloodstream, and its fasting blood levels are much lower (~0.005 mM) than glucose (~5.5 mM) under normal physiological conditions. Therefore, it remains unclear where fructose is derived from and how cancer cells acquire a sufficient amount of fructose to supplement their energy needs. Here we report that the polyol pathway is active in cancer cells and is capable of converting up to 50% of glucose into fructose, resulting in enhanced glycolysis and ATP production. Inhibition of the polyol pathway severely decreased fructose production in cancer cells and suppressed their glycolysis, ATP production, and growth rate. Furthermore, we determined that the glucose transporter, SLC2A8/GLUT8, was a crucial transporter to export intracellular fructose outside cells. Taken together, our study identified an overlooked but critically essential fructose-producing pathway in cancer cells as an integral part of their metabolic reprogramming leading to enhanced glycolysis, cell proliferation, and malignancy.

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supporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Fructose Metabolism Contributes to the Warburg effect

Han

Wang

Zhang

et al. 2020

Preprint

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“…GLUT5 is signi cantly upregulated in tumors from patients with colon, lung, and breast adenocarcinoma, acute myeloid leukemia, ovarian carcinoma, and glioma where it contributes to malignancy and poor survival (16,21,23,(25)(26)(27)27). Many of these studies investigated fructose metabolism in the absence of glucose, using a wide range of fructose concentrations (ref 22 Our data con rms that GLUT5 overexpression is su cient to promote cellular proliferation in fructose, but the abundance of the GLUT5 transcript in our initial pro ling did not predict the fructolytic index across cell lines. For example, H508 (fructolytic) and RKO (non-fructolytic) cells are from the same colorectal origin with similar levels of GLUT5 yet have vastly different abilities to proliferate in fructose.…”

Section: Discussionmentioning

confidence: 99%

“…Tumors can also metabolize fructose. This has been shown for a variety of tumor 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: (27,28)). In many of these cases, fructose has been shown to enter the cell through a membrane transporter, GLUT5, and then undergo metabolism into downstream glycolytic intermediates.…”

mentioning

confidence: 85%

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

Liang

Taylor

Nahiyaan

et al. 2021

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 acquire the ability to 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: Live cell imaging and crystal violet assays were used to characterize the ability of several cell lines (RKO, H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e. the fructolytic ability). Fructose metabolism gene expression was determined by RT-qPCR and western blot for each cell line. A positive selection approach was used to “train” non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq was performed on parental and trained PC3 cells to find key transcripts associated with fructolytic ability. A CRISPR-cas9 plasmid containing KHK-specific sgRNA was transfected in 293T cells to generate KHK -/- cells. Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in cells. Metabolic profiling was done with Seahorse metabolic flux analysis as well as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 2-deoxyglucose in media containing either fructose or glucose. Results: We found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine the fructolytic ability. However, cells cultured chronically in fructose can develop fructolytic ability. SLC2A5, encoding the fructose transporter, GLUT5, was specifically upregulated in these cells. Overexpression of GLUT5 in non-fructolytic cells enabled 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 the limiting factor for fructose-mediated cell proliferation. We further demonstrate that cellular proliferation with fructose is independent of KHK.

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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: 87%

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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GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling

Cited by 75 publications

References 59 publications

Fructose Metabolism Contributes to the Warburg effect

Fructose Metabolism Contributes to the Warburg effect

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

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

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