Fructose Metabolism Contributes to the Warburg effect

Abstract

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.

IsoSolve: An Integrative Framework to Improve Isotopic Coverage and Consolidate Isotopic Measurements by Mass Spectrometry and/or Nuclear Magnetic Resonance

“…Stable-isotope labeling experiments are widely used to investigate metabolic networks in the fields of systems biology, , biotechnology, − and biomedical research. , The most effective approach is to combine 13 C-labeling strategies with a detailed analysis of isotope incorporation into metabolites, as measured by mass spectrometry (MS) and/or nuclear magnetic resonance (NMR) spectroscopy . MS provides global isotopic information by quantifying the proportions of molecules with different numbers of tracer isotopes (isotopologue distributions), , while NMR provides positional information on tracer incorporation at specific positions in the molecules (isotopomer distributions) − by exploiting the 1 H and 13 C nuclei via nondecoupled experimentssuch as homonuclear 1 H- 1 H-TOCSY and heteronuclear 1 H- 13 C-HSQC experiments.…”

IsoSolve: an integrative framework to improve isotopic coverage and consolidate isotopic measurements by MS and/or NMR

“…Stable-isotope labeling experiments are widely used to investigate metabolic networks in the fields of systems biology [1][2] , biotechnology [3][4] and biomedical research [5][6] . The most effective approach is to combine 13 C-labeling strategies with a detailed analysis of isotope incorporation into metabolites, as measured by mass spectrometry (MS) and/or nuclear magnetic resonance (NMR) spectroscopy 7 .…”

“…Stable-isotope labeling experiments are widely used to investigate metabolic networks in the fields of systems biology 1–2 , biotechnology 3–4 and biomedical research 5–6 . The most effective approach is to combine 13 C-labeling strategies with a detailed analysis of isotope incorporation into metabolites, as measured by mass spectrometry (MS) and/or nuclear magnetic resonance (NMR) spectroscopy 7. MS provides global isotopic information by quantifying the proportions of molecules with different numbers of tracer isotopes (isotopologue distributions) 8–9 , while NMR provides positional information on tracer incorporation at specific positions in the molecules (isotopomer distributions) 10–13 by exploiting the 1 H and 13 C nuclei via non-decoupled experiments – such as homonuclear 1 H- 1 H-TOCSY and heteronuclear 1 H- 13 C-HSQC experiments.…”