Conserved metabolic energy production pathways govern Eiger/TNF-induced nonapoptotic cell death
- 7 November 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (47), 18977-18982
- https://doi.org/10.1073/pnas.1103242108
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.Keywords
This publication has 50 references indexed in Scilit:
- Oncogenic Ras Diverts a Host TNF Tumor Suppressor Activity into Tumor PromoterDevelopmental Cell, 2010
- Necroptosis as an alternative form of programmed cell deathCurrent Opinion in Cell Biology, 2010
- Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced InflammationCell, 2009
- Regenerative Growth in Drosophila Imaginal Discs Is Regulated by Wingless and MycDevelopmental Cell, 2009
- Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-αCell, 2009
- Intrinsic Tumor Suppression and Epithelial Maintenance by Endocytic Activation of Eiger/TNF Signaling in DrosophilaDevelopmental Cell, 2009
- Identification of a Molecular Signaling Network that Regulates a Cellular Necrotic Cell Death PathwayCell, 2008
- Keap1/Nrf2 Signaling Regulates Oxidative Stress Tolerance and Lifespan in DrosophilaDevelopmental Cell, 2008
- Tumor Suppressor CYLD Regulates JNK-Induced Cell Death in DrosophilaDevelopmental Cell, 2007
- Evolution of TNF Signaling MechanismsCurrent Biology, 2002