BubR1 is required for a sustained mitotic spindle checkpoint arrest in human cancer cells treated with tubulin-targeting pyrrolo-1,5-benzoxazepines

Lisa M Greene, Giuseppe Campiani, Mark Lawler, D Clive Williams, Daniela M Zisterer, Mark Lawler

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Intrinsic or acquired resistance to chemotherapy is a major clinical problem that has evoked the need to develop innovative approaches to predict and ultimately reverse drug resistance. A prolonged G(2)M arrest has been associated with apoptotic resistance to various microtubule-targeting agents (MTAs). In this study, we describe the functional significance of the mitotic spindle checkpoint proteins, BubR1 and Bub3, in maintaining a mitotic arrest after microtubule disruption by nocodazole and a novel series of MTAs, the pyrrolo-1,5-benzoxazepines (PBOXs), in human cancer cells. Cells expressing high levels of BubR1 and Bub3 (K562, MDA-MB-231, and HeLa) display a prolonged G(2)M arrest after exposure to MTAs. On the other hand, cells with low endogenous levels of mitotic spindle checkpoint proteins (SK-BR-3 and HL-60) transiently arrest in mitosis and undergo increased apoptosis. The phosphorylation of BubR1 correlated with PBOX-induced G(2)M arrest in four cell lines tested, indicating an active mitotic spindle checkpoint. Gene silencing of BubR1 by small interfering RNA interference reduced PBOX-induced G(2)M arrest without enhancing apoptotic efficacy. Further analysis demonstrated that PBOX-treated BubR1-depleted cells were both mononucleated and multinucleated with a polyploid DNA content, suggesting a requirement for BubR1 in cytokinesis. Taken together, these results suggest that BubR1 contributes to the mitotic checkpoint induced by the PBOXs.

Original languageEnglish
Pages (from-to)419-30
Number of pages12
JournalMolecular Pharmacology
Volume73
Issue number2
DOIs
Publication statusPublished - Feb 2008

Keywords

  • Apoptosis
  • Cell Line, Tumor
  • HL-60 Cells
  • Humans
  • K562 Cells
  • Mitosis
  • Neoplasms
  • Oxazepines
  • Protein-Serine-Threonine Kinases
  • Pyrroles
  • Spindle Apparatus
  • Tubulin

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