G1 and G2 cell-cycle arrest following microtubule depolymerization in human breast cancer cells

被引:172
作者
Blajeski, AL
Phan, VA
Kottke, TJ
Kaufmann, SH
机构
[1] Mayo Clin & Mayo Fdn, Div Oncol Res, Rochester, MN 55905 USA
[2] Mayo Grad Sch, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA
[3] Mayo Grad Sch, Tumor Biol Program, Rochester, MN USA
关键词
D O I
10.1172/JCI200213275
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Microtubule-depolymerizing agents are widely used to synchronize cells, screen for mitotic checkpoint defects, and treat cancer. The present study evaluated the effects of these agents on normal and malignant human breast cell lines. After treatment with 1 muM nococlazole, seven of ten breast cancer lines (type A cells) arrested in mitosis, whereas the other three (type B cells) did not. Similar effects were observed with 100 nM vincristine or colchicine. Among five normal mammary epithelial isolates, four exhibited type A behavior and one exhibited type B behavior. Further experiments revealed that the type B cells exhibited a biphasic dose-response curve, with mitotic arrest at low drug concentrations (100 nM nocodazole or 6 nM vincristine) that failed to depolymerize microtubules and a p53-independent p21(waf1/cip1)-associated G(1) and G(2) arrest at higher concentrations (1 muM nocodazole or 100 nM vincristine) that depolymerized microtubules. Collectively, these observations provide evidence for coupling of premitotic cell-cycle progression to microtubule integrity in some breast cancer cell lines (representing a possible "microtubule integrity checkpoint") and suggest a potential explanation for the recently reported failure of some cancer cell tines to undergo nocodazole-induced mitotic arrest despite intact mitotic checkpoint proteins.
引用
收藏
页码:91 / 99
页数:9
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