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Abstract The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage‐induced cell death. Mechanistically, FAO induction increases cellular acetyl‐CoA levels and promotes N‐alpha‐acetylation of caspase‐2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator‐activated receptor α (PPARα), accelerated hypoxia‐inducible factor‐1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity‐driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.

Superoxide dismutase (SOD) converts superoxide radical to H(2)O(2), which is in turn broken down to water and oxygen by catalase. Thus, SOD and catalase constitute the first coordinated unit of defence against reactive oxygen species. A wide variety of chemical and environmental factors are known to induce these antioxidant enzymes. Here, we examined the effect of ginseng saponins on the induction of SOD and catalase gene expression. To explore this possibility, the upstream regulatory promoter region of Cu/Zn superoxide dismutase (SOD1) and catalase genes were linked to the chloramphenicol acetyltransferase (CAT) structural gene and introduced into human hepatoma HepG2 cells. Total saponin and panaxatriol did not activate the transcription of SOD1 and catalase genes but panaxadiol increased the transcription of these genes about 2-3 fold. Among the panaxadiol ginsenosides, the Rb(2) subfraction appeared to be a major inducer of SOD1 and catalase genes. The specificity of the Rb(2) effect was further confirmed by time course- and dose-dependent induction experiments. These results suggest that the panaxadiol fraction and its ginsenosides could induce the antioxidant enzymes which are important for maintaining cell viability by lowering the level of oxygen radical generated from intracellular metabolism., (Copyright 1999 John Wiley & Sons, Ltd.)