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(-)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: role of topoisomerase IIα inhibition and reactive oxygen species.
- Source :
-
Toxicology [Toxicology] 2013 Mar 08; Vol. 305, pp. 1-9. Date of Electronic Publication: 2013 Jan 08. - Publication Year :
- 2013
-
Abstract
- Previously, we reported that (-)-xanthatin, a naturally occurring xanthanolide present in the Cocklebur plant, exhibits potent anti-proliferative effects on human breast cancer cells, accompanied by an induction of the growth arrest and DNA damage-inducible gene 45γ (GADD45γ), recognized recently as a novel tumor suppressor gene. However, the mechanisms mediating this activation were unknown. Topoisomerase IIα (Topo IIα) inhibition has been reported to produce a cell death response accompanied by an atypical DNA laddering fragmentation profile, similar to that noted previously for (-)-xanthatin. Therefore we hypothesized that (-)-xanthatin's GADD45γ activation was mediated through the Topo IIα pathway. Here, we identify that (-)-xanthatin does function as a catalytic inhibitor of Topo IIα, promoting DNA damage. In addition, reactive oxygen species (ROS) were elevated in cells treated with this agent. Mechanistically, it was determined that the induced levels of GADD45γ mRNA resulting from (-)-xanthatin exposures were stabilized by coordinately produced ROS, and that the consequent induction of GADD45γ mRNA, GADD45γ protein and ROS generation were abrogated by co-treatment with N-acetyl-l-cysteine. Taken together, the data support the concept that Topo IIα inhibition by (-)-xanthatin is a trigger that stimulates expression of DNA damage-inducible GADD45γ mRNA and that concomitantly produced ROS act downstream to further enhance the GADD45γ mRNA/GADD45γ protein induction process, resulting in breast cancer cell death.<br /> (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Acetylcysteine pharmacology
Antigens, Neoplasm drug effects
Blotting, Western
Cell Line, Tumor
DNA Damage
DNA Topoisomerases, Type II drug effects
DNA, Neoplasm drug effects
DNA-Binding Proteins drug effects
Female
Free Radical Scavengers pharmacology
Glutathione metabolism
Half-Life
Humans
Intracellular Signaling Peptides and Proteins genetics
RNA, Messenger biosynthesis
RNA, Messenger genetics
Up-Regulation drug effects
GADD45 Proteins
Antigens, Neoplasm physiology
DNA Topoisomerases, Type II physiology
DNA-Binding Proteins physiology
Furans pharmacology
Insecticides pharmacology
Intracellular Signaling Peptides and Proteins biosynthesis
Reactive Oxygen Species metabolism
Topoisomerase II Inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3185
- Volume :
- 305
- Database :
- MEDLINE
- Journal :
- Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 23313378
- Full Text :
- https://doi.org/10.1016/j.tox.2012.12.019