RT Journal Article
SR Electronic
T1 Dependence of Paclitaxel Sensitivity on a Functional Spindle Assembly Checkpoint
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 2502
OP 2508
DO 10.1158/0008-5472.CAN-03-2013
VO 64
IS 7
A1 Sudo, Tamotsu
A1 Nitta, Masayuki
A1 Saya, Hideyuki
A1 Ueno, Naoto T.
YR 2004
UL http://cancerres.aacrjournals.org/content/64/7/2502.abstract
AB 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.