title: Metabolomic profile of glycolysis and the pentose phosphate pathway identifies the central role of glucose-6-phosphate dehydrogenase in clear cell-renal cell carcinoma.
abstract: The analysis of cancer metabolome has shown that proliferating tumor cells require a large quantities of different nutrients in order to support their high rate of proliferation. In this study we analyzed the metabolic profile of glycolysis and the pentose phosphate pathway (PPP) in human clear cell-renal cell carcinoma (ccRCC) and evaluate the role of these pathways in sustaining cell proliferation, maintenance of NADPH levels, and production of reactive oxygen species (ROS). Metabolomic analysis showed a clear signature of increased glucose uptake and utilization in ccRCC tumor samples. Elevated levels of glucose-6-phosphate dehydrogenase (G6PDH) in association with higher levels of PPP-derived metabolites, suggested a prominent role of this pathway in RCC-associated metabolic alterations. G6PDH inhibition, caused a significant decrease in cancer cell survival, a decrease in NADPH levels, and an increased production of ROS, suggesting that the PPP plays an important role in the regulation of ccRCC redox homeostasis. Patients with high levels of glycolytic enzymes had reduced progression-free and cancer-specific survivals as compared to subjects with low levels. Our data suggest that oncogenic signaling pathways may promote ccRCC through rerouting the sugar metabolism. Blocking the flux through this pathway may serve as a novel therapeutic target.
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lucarelli
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Galleggiante
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Rutigliano
authors.affiliation: Department of Pathology, University of Foggia, Foggia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanguedolce
authors.affiliation: Department of Pathology, University of Foggia, Foggia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Cagiano
authors.affiliation: Department of Pathology, University of Foggia, Foggia, Italy.
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Bufo
authors.affiliation: Department of Pathology, University of Bari, Bari, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Lastilla
authors.affiliation: Department of Pathology, University of Bari, Bari, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari, Bari, Italy.|National Cancer Institute "Giovanni Paolo II", Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giglio
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Serino
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vavallo
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Bettocchi
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Selvaggi
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Battaglia
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Ditonno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation / Q000502:physiology; D002853:Chromatography, Liquid; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D017382:Reactive Oxygen Species; D009249:NADP; D005954:Glucosephosphate Dehydrogenase
keywords: G6PDH; glycolysis; metabolomics; pentose phosphate pathway; renal cell carcinoma