Procaspase-3-activating compound 1 stabilizes hypoxia-inducible factor 1? and induces DNA damage by sequestering ferrous iron.

ABSTRACT: 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? (HIF1?) 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? hydroxylation and upregulated HIF1? target genes. In addition, DNA damage, G₁/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? stabilization and DNA damage by sequestering ferrous iron.

SUBMITTER: Li F 

PROVIDER: S-EPMC6172261 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature