Alternative metabolic pathways for energy supply and resistance to apoptosis in Fanconi anaemia.
Deregulation of control of the apoptotic process in Fanconi anaemia (FA) appears to be one of the main features of this disease at the cellular level. We show here that FA cells are resistant to treatments with rhodamine-1,2,3 and doxycycline, which both interfere with mitochondrial functionality by different mechanisms. In contrast, normal lymphoblastoid cells are severely affected by these treatments, which result in acute ATP depletion and a significant enhancement of the fraction of cells undergoing apoptotic cell death. FA cells are very sensitive to the action of 2-deoxy-D-glucose (2dG) and iodoacetic acid (IAA), two inhibitors of glycolytic metabolism. The ability of FA cells to sustain metabolic insults interfering with energy production and balance may be linked with the pathological manifestations of the disease, including susceptibility to acute myeloid leukemia. These findings suggest that FA genes may be involved in a pathway that mediates a protective response to stress. We suggest that a peculiar metabolic regulation in FA cells could explain both defective apoptosis and susceptibility to oxidative stress.
Bogliolo
Massimo
M
Laboratory of Mutagenesis, National Cancer Research Institute, IST, Lgo R. Benzi 10, 16132 Genoa, Italy.
Borghini
Silvia
S
Abbondandolo
Angelo
A
Degan
Paolo
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D003847:Deoxyglucose / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism; D005199:Fanconi Anemia / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D052217:Fanconi Anemia Complementation Group A Protein; D051856:Fanconi Anemia Complementation Group Proteins; D020022:Genetic Predisposition to Disease; D006019:Glycolysis / Q000187:drug effects; D004854:Herpesvirus 4, Human; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D019807:Iodoacetic Acid / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects; D009687:Nuclear Proteins; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics / Q000502:physiology; D020112:Rhodamine 123 / Q000494:pharmacology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D020112:Rhodamine 123; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D004318:Doxycycline; D019807:Iodoacetic Acid