Abstract

Clinical localization of primary tumors and sites of metastasis by positron emission tomography (PET) is based on the enhanced cellular uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (FDG). In prostate cancer (PCa), however, PET-FDG imaging has shown limited clinical applicability, suggesting that PCa cells may utilize hexoses other than glucose, such as fructose, as the preferred energy source. Our previous studies suggested that PCa cells overexpress fructose transporters but not glucose transporters compared to benign cells. Here we focused on validating the functional expression of fructose transporters and determining whether fructose can modulate the biology of PCa cells in vitro and in vivo. Fructose transporters Glut-5 and Glut-9 were significantly upregulated in clinical specimens of PCa when compared to their benign counterparts. Fructose levels in the serum of patients with PCa were significantly higher than healthy subjects. Functional expression of fructose transporters was confirmed in PCa cell lines. A detailed kinetic characterization indicated that Glut-5 represents the main functional contributor in mediating fructose transport in PCa cells. Fructose stimulated proliferation and invasion of PCa cells in vitro. In addition, dietary fructose increased the growth of PCa cell line-derived xenograft tumors and promoted PCa cell proliferation in patient-derived xenografts. Gene set enrichment analysis confirmed that fructose stimulation enriched for proliferation-related pathways in PCa cells. These results demonstrate that fructose promotes PCa cell growth and aggressiveness in vitro and in vivo and may represent an alternative energy source for PCa cells.