Dependence of Paclitaxel Sensitivity on a Functional Spindle Assembly Checkpoint

Tamotsu Sudo, Masayuki Nitta, Hideyuki Saya, Naoto T. Ueno

Research output: Contribution to journalArticle

205 Citations (Scopus)

Abstract

Paclitaxel stabilizes microtubules, causing mitotic arrest and activating the spindle assembly checkpoint. We determined whether suppression of the checkpoint genes Mad2 and BubR1 affects paclitaxel resistance and whether overexpression of Mad2 protein in checkpoint-defective cells enhances paclitaxel sensitivity. Suppression of Mad2 and BubR1 in paclitaxel-treated cancer cells abolished checkpoint function, resulting in paclitaxel resistance that correlated with suppression of cyclin-dependent kinase-1 activity. In contrast, overexpression of Mad2 in cells with a checkpoint defect attributable to low Mad2 expression restored checkpoint function, resulting in enhanced paclitaxel sensitivity that correlated with enhanced cyclin-dependent kinase-1 activity. However, overexpression of Mad2 failed to enhance paclitaxel sensitivity via checkpoint activation in Mad2-independent checkpoint-defective and -intact cells. Thus, checkpoint function is required for paclitaxel sensitivity. These findings show that any molecules that could interfere with the spindle assembly checkpoint could generate paclitaxel resistance in any patient.

Original languageEnglish
Pages (from-to)2502-2508
Number of pages7
JournalCancer Research
Volume64
Issue number7
DOIs
Publication statusPublished - 2004 Apr 1
Externally publishedYes

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M Phase Cell Cycle Checkpoints
Paclitaxel
CDC2 Protein Kinase
Mad2 Proteins
Microtubules

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dependence of Paclitaxel Sensitivity on a Functional Spindle Assembly Checkpoint. / Sudo, Tamotsu; Nitta, Masayuki; Saya, Hideyuki; Ueno, Naoto T.

In: Cancer Research, Vol. 64, No. 7, 01.04.2004, p. 2502-2508.

Research output: Contribution to journalArticle

Sudo, Tamotsu ; Nitta, Masayuki ; Saya, Hideyuki ; Ueno, Naoto T. / Dependence of Paclitaxel Sensitivity on a Functional Spindle Assembly Checkpoint. In: Cancer Research. 2004 ; Vol. 64, No. 7. pp. 2502-2508.
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