Journal
CELL DEATH & DISEASE
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-1038-3
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Funding
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2012ZX09301-001, 2012ZX09301-003]
- National Natural Science Foundation of China [81430090, 81773790]
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University [FAMP201708K]
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Procaspase-3-activating compound 1 (PAC-1) induces procaspase-3 activation via zinc chelation. However, whether PAC-1 employs other mechanisms remains unknown. Here we systematically screened for potent PAC-1 targets using 29 enhanced green fluorescent protein-labeled reporter cell lines and identified hypoxia-inducible factor 1 alpha (HIF1 alpha) and RAD51 pathways as PAC-1 targets. These results were verified in HepG2 cells and two other cancer cell lines. Mechanistically, PAC-1 specifically blocked HIF1 alpha hydroxylation and upregulated HIF1 alpha target genes. In addition, DNA damage, G(1)/S cell cycle arrest, and the inhibition of DNA synthesis were induced following PAC-1 administration. Interestingly, by using ferrozine-iron sequestration and iron titration assays, we uncovered the iron sequestering capacity of PAC-1. Additionally, the expression levels of iron shortage-related genes were also increased in PAC-1 treated cells, and iron (II) supplementation reversed all of the observed cellular responses. Thus, our results indicate that PAC-1 induces HIF1 alpha stabilization and DNA damage by sequestering ferrous iron.
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