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Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
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Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging

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Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with

L A Hazlehurst1, N Valkov, L Wisner

  • 1Department of Interdisciplinary Oncology and Clinical Investigations Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA.

Blood
|September 6, 2001
PubMed

Insights

Fibronectin adhesion via beta1 integrins protects lymphoma cells from topoisomerase II inhibitor DNA damage. This protection involves reduced topoisomerase II activity and altered nuclear binding of topoisomerase IIbeta.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Drug Resistance Mechanisms

Background:

  • Previous studies demonstrated that myeloma cell adhesion to fibronectin (FN) via beta1 integrins confers resistance to cytotoxic drugs.
  • Topoisomerase (topo) II inhibitors are crucial in cancer therapy, inducing apoptosis through DNA damage.

Purpose of the Study:

  • To investigate whether U937 human histiocytic lymphoma cell adhesion to FN influences resistance to topoisomerase II inhibitors.
  • To elucidate the mechanisms underlying cellular-adhesion-mediated drug resistance in U937 cells.

Main Methods:

  • Neutral comet assay to quantify drug-induced DNA double-strand breaks.
  • Assessment of topoisomerase II activity and nuclear protein levels.
  • Confocal microscopy to analyze the nuclear localization of topoisomerase IIbeta.

Main Results:

  • Adhesion to FN via beta1 integrins reduced DNA double-strand breaks induced by mitoxantrone and etoposide by 40-60%.
  • This adhesion correlated with decreased topoisomerase II activity and reduced levels of salt-extractable nuclear topoisomerase IIbeta.
  • Topoisomerase IIbeta showed tighter binding to the nucleus in FN-adhered cells.

Conclusions:

  • Fibronectin adhesion, mediated by beta1 integrins, confers a survival advantage to U937 cells against topoisomerase II inhibitors.
  • Protection is achieved by reducing topoisomerase II activity, secondary to altered nuclear distribution and binding of topoisomerase IIbeta.

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