Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells

Justin Wray, Elizabeth A. Williamson, Melanie Royce, Montaser Shaheen, Brian D. Beck, Suk Hee Lee, Jac A. Nickoloff, Robert Hromas

Producción científica: Articlerevisión exhaustiva

42 Citas (Scopus)

Resumen

DNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIα (Topo IIα) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is incomplete, which occurs when Topo IIα is inhibited by chemotherapy agents such as the anthracyclines and epididophyllotoxins. We recently demonstrated that the DNA repair component Metnase (also called SETMAR) enhances Topo IIα-mediated decatenation, and hypothesized that Metnase could mediate resistance to Topo IIα inhibitors. Here we show that Metnase interacts with Topo IIα in breast cancer cells, and that reducing Metnase expression significantly increases metaphase decatenation checkpoint arrest. Repression of Metnase sensitizes breast cancer cells to Topo IIα inhibitors, and directly blocks the inhibitory effect of the anthracycline adriamycin on Topo IIα-mediated decatenation in vitro. Thus, Metnase may mediate resistance to Topo IIα inhibitors, and could be a biomarker for clinical sensitivity to anthracyclines. Metnase could also become an important target for combination chemotherapy with current Topo IIα inhibitors, specifically in anthracycline-resistant breast cancer.

Idioma originalEnglish (US)
Número de artículoe5323
PublicaciónPloS one
Volumen4
N.º4
DOI
EstadoPublished - abr 24 2009
Publicado de forma externa

ASJC Scopus subject areas

  • General
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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