(-)-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

Shuso Takeda, Momoko Noguchi, Kazumasa Matsuo, Yasuhiro Yamaguchi, Taichi Kudo, Hajime Nishimura, Yoshiko Okamoto, Toshiaki Amamoto, Mitsuru Shindo, Curtis J. Omiecinski, Hironori Aramaki

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalToxicology
Volume305
DOIs
Publication statusPublished - Mar 8 2013

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Type II DNA Topoisomerase
Tumor Suppressor Genes
DNA Damage
Tumors
Reactive Oxygen Species
Up-Regulation
Genes
Cells
Breast Neoplasms
DNA
Growth
Messenger RNA
Cell death
Xanthium
Cell Death
xanthatin
Acetylcysteine
Chemical activation
Topoisomerase II Inhibitors
DNA Fragmentation

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

(-)-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. / Takeda, Shuso; Noguchi, Momoko; Matsuo, Kazumasa; Yamaguchi, Yasuhiro; Kudo, Taichi; Nishimura, Hajime; Okamoto, Yoshiko; Amamoto, Toshiaki; Shindo, Mitsuru; Omiecinski, Curtis J.; Aramaki, Hironori.

In: Toxicology, Vol. 305, 08.03.2013, p. 1-9.

Research output: Contribution to journalArticle

Takeda, S, Noguchi, M, Matsuo, K, Yamaguchi, Y, Kudo, T, Nishimura, H, Okamoto, Y, Amamoto, T, Shindo, M, Omiecinski, CJ & Aramaki, H 2013, '(-)-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', Toxicology, vol. 305, pp. 1-9. https://doi.org/10.1016/j.tox.2012.12.019
Takeda, Shuso ; Noguchi, Momoko ; Matsuo, Kazumasa ; Yamaguchi, Yasuhiro ; Kudo, Taichi ; Nishimura, Hajime ; Okamoto, Yoshiko ; Amamoto, Toshiaki ; Shindo, Mitsuru ; Omiecinski, Curtis J. ; Aramaki, Hironori. / (-)-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. In: Toxicology. 2013 ; Vol. 305. pp. 1-9.
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