title: Conserved metabolic energy production pathways govern Eiger/TNF-induced nonapoptotic cell death.
abstract: Caspase-independent cell death is known to be important in physiological and pathological conditions, but its molecular regulation is not well-understood. Eiger is the sole fly ortholog of TNF. The ectopic expression of Eiger in the developing eye primordium caused JNK-dependent but caspase-independent cell death. To understand the molecular basis of this Eiger-induced nonapoptotic cell death, we performed a large-scale genetic screen in Drosophila for suppressors of the Eiger-induced cell death phenotype. We found that molecules that regulate metabolic energy production are central to this form of cell death: it was dramatically suppressed by decreased levels of molecules that regulate cytosolic glycolysis, mitochondrial β-oxidation of fatty acids, the tricarboxylic acid cycle, and the electron transport chain. Importantly, reducing the expression of energy production-related genes did not affect the cell death triggered by proapoptotic genes, such as reaper, hid, or debcl, indicating that the energy production-related genes have a specific role in Eiger-induced nonapoptotic cell death. We also found that energy production-related genes regulate the Eiger-induced cell death downstream of JNK. In addition, Eiger induced the production of reactive oxygen species in a manner dependent on energy production-related genes. Furthermore, we showed that this cell death machinery is involved in Eiger's physiological function, because decreasing the energy production-related genes suppressed Eiger-dependent tumor suppression, an intrinsic mechanism for removing tumorigenic mutant clones from epithelia by inducing cell death. This result suggests a link between sensitivity to cell death and metabolic activity in cancer.
authors: Department of Physiology,  Keio University School of Medicine, Tokyo 160-8582,  Japan.
authors: Hiroshi
authors: H
authors: Kanda
authors: Tatsushi
authors: T
authors: Igaki
authors: Hideyuki
authors: H
authors: Okano
authors: Masayuki
authors: M
authors: Miura
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D016923:Cell Death / Q000502:physiology*; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology*; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005838:Genotype; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C464573:egr protein, Drosophila; D000255:Adenosine Triphosphate