Conserved metabolic energy production pathways govern Eiger/TNF-induced nonapoptotic cell death

Hiroshi Kanda, Tatsushi Igaki, Hideyuki Okano, Masayuki Miura

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31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)18977-18982
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number47
DOIs
Publication statusPublished - 2011 Nov 22

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Keywords

  • Chromosomal deficiency screen
  • Necroptosis
  • Scribble
  • Tumor

ASJC Scopus subject areas

  • General

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