Abstract
2-fluoro-2-deoxy-D-glucose (FDG), labeled with 18F radioisotope, is the most common imaging agent used for positron emission tomography (PET) in oncology. However, little is known about the cellular effects of FDG. Another glucose analogue, 2-deoxy-D-glucose (2DG), has been shown to affect many cellular functions, including intracellular transport and lipid metabolism, and has been found to improve the efficacy of cancer chemotherapeutic agents in vivo. Thus, in the present study, we have investigated cellular effects of FDG with the focus on changes in cellular lipids and intracellular transport. By quantifying more than 200 lipids from 17 different lipid classes in HEp-2 cells and by analyzing glycosphingolipids from MCF-7, HT-29 and HBMEC cells, we have discovered that FDG treatment inhibits glucosylceramide synthesis and thus reduces cellular levels of glycosphingolipids. In addition, in HEp-2 cells the levels and/or species composition of other lipid classes, namely diacylglycerols, phosphatidic acids and phosphatidylinositols, were found to change upon treatment with FDG. Furthermore, we show here that FDG inhibits retrograde Shiga toxin transport and is much more efficient in protecting cells against the toxin than 2DG. In summary, our data reveal novel effects of FDG on cellular transport and glycosphingolipid metabolism, which suggest a potential clinical application of FDG as an adjuvant for cancer chemotherapy.
Highlights
2-fluoro-2-deoxy-D-glucose (FDG) is a structural analogue of glucose where the hydroxyl group at the C-2 position is replaced by a fluorine atom. [18F]FDG, with its incorporated 18F radioisotope, is the most common imaging agent used for positron emission tomography (PET) in the clinic. [18F]FDG-PET has been established as a standard technique for staging and monitoring of multiple cancers
The use of [18F]FDG-PET in oncology is based on an increased uptake and metabolism of glucose in cancer cells, which leads to higher accumulation of [18F] FDG in tumors compared to surrounding tissues
We have previously reported a novel effect of the glucose analogue 2DG on the intracellular transport of Shiga toxins (Stx)
Summary
2-fluoro-2-deoxy-D-glucose (FDG) is a structural analogue of glucose where the hydroxyl group at the C-2 position is replaced by a fluorine atom. [18F]FDG, with its incorporated 18F radioisotope, is the most common imaging agent used for positron emission tomography (PET) in the clinic. [18F]FDG-PET has been established as a standard technique for staging and monitoring of multiple cancers (for review see [1]). It has not been studied whether FDG affects any of these processes. Diphtheria toxin (DT), which binds to the heparin-binding epidermal growth factor precursor (pro-HB-EGF) [21], is directly translocated from endosomes into the cytosol upon low pH-induced conformational change [22], and does not require transport to ER for its cytotoxic action
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