title: Fructose sensitizes Jurkat cells oxidative stress-induced apoptosis via caspase-dependent and caspase-independent mechanisms.
abstract: Whether fructose (FRU), as the sole energy source, confers a metabolic advantage on cancer cells against noxious stimuli is unknown. The aim of this study was to evaluate the effects of low (11 mM), moderate (25 mM), and high (55 mM) FRU concentrations alone or in combination with rotenone (ROT) or doxorubicin (DOX) in Jurkat cells, an acute lymphoblastic leukemia cell model. Glucose (GLU) was used as a control. Using different cell analysis techniques, we demonstrated that FRU was predominantly metabolized via oxidative phosphorylation (∼95%) (i.e., lactate production was reduced >120-fold), resulting in endogenous oxidative stress-induced conditions. The cells were characterized by generation of O2•-(43%)/ H2O2(40%) and activation of NF-κB (∼95-fold increase, fi), c-Jun-N terminal kinase (JNK), p53 (40-fi), and c-Jun (9-fi). In addition, we observed a loss of ΔΨm(10%), activation of caspase-3 (50-fi) and apoptosis-inducing factor (AIF, 2-fi), and condensation and fragmentation of the nuclei [20% by acridine orange/ethidium bromide/Hoechst (AO/EB/H) staining, 15% by flow cytometry] compared to those of GLU 11 at 24 h. Although DOX killed Jurkat cells independent of sugar content in the culture medium, leukemic cells in low, but not high, FRU were extremely sensitive to ROT. Taken together, our findings suggest that Jurkat cells are more susceptible to cell death if forced to shift from GLU metabolism (i.e., aerobic glycolysis) to FRU metabolism (i.e., oxidative phosphorylation) after treatment with mitochondria-targeting molecules. These observations may help elucidate the cell death mechanism of leukemic cells cultured in FRU.
authors.affiliation: Neuroscience Research Group, Faculty of Medicine, Medical Research Institute, University of Antioquia (UdeA), Calle 70 No. 52-21 and Calle 62 # 52-59, Building 1, Room 412, SIU Medellin, Colombia.
authors.forename: Viviana
authors.initials: V
authors.lastname: Diaz-Aguirre
authors.affiliation: Neuroscience Research Group, Faculty of Medicine, Medical Research Institute, University of Antioquia (UdeA), Calle 70 No. 52-21 and Calle 62 # 52-59, Building 1, Room 412, SIU Medellin, Colombia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Velez-Pardo
authors.affiliation: Neuroscience Research Group, Faculty of Medicine, Medical Research Institute, University of Antioquia (UdeA), Calle 70 No. 52-21 and Calle 62 # 52-59, Building 1, Room 412, SIU Medellin, Colombia. marlene.jimenez@udea.edu.co.
authors.forename: Marlene
authors.initials: M
authors.lastname: Jimenez-Del-Rio
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D005632:Fructose / Q000008:administration & dosage / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D012402:Rotenone / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012402:Rotenone; D013481:Superoxides; D005632:Fructose; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D005947:Glucose
keywords: AIF; NF-κB; apoptosis; c-Jun; caspase-3; fructose; oxidative stress; p53