Abstract
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.
Highlights
Topo IIa inhibitors such as anthracyclines or epididophyllotoxins are important agents in the treatment of human malignancy [1,2,3]
Lung and bladder cancers proceed through the decatenation checkpoints even in the presence of high levels of Topo IIa inhibitors, and this was thought to be secondary to a failure of the cell cycle arrest machinery [13,14]
We report here that Metnase interacts with Topo IIa in breast cancer cells, promotes progression through metaphase in breast cancer cells treated with a Topo IIa inhibitor, sensitizes breast cancer cells to the anthracycline adriamycin and the epididophyllotoxin VP16, and directly blocks Topo IIa inhibition by adriamycin in vitro
Summary
Topo IIa inhibitors such as anthracyclines or epididophyllotoxins are important agents in the treatment of human malignancy [1,2,3]. We hypothesized that Metnase may mediate the resistance of malignant cells to Topo IIa inhibitors, and chose to test this in breast cancer cells because anthracyclines are among the most important agents in the treatment of this disease [1,20,21,22].
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