Abstract
Antimicrotubule agents are commonly used chemotherapy drugs for the treatment of breast and other cancers. However, these agents have variable activity partly because of microtubule regulatory proteins. Stathmin, an 18-kDa phosphoprotein that promotes microtubule depolymerization, was found to be frequently overexpressed in breast cancer. We previously identified stathmin-mediated mechanisms of resistance to antimicrotubule agents, including altered drug binding and delayed transit from G2 into M phase, where these agents are effective in disrupting microtubule dynamics. We hypothesized that by reversing stathmin-mediated depolymerization of microtubules or by promoting entry into mitosis, this could increase sensitivity to antimicrotubule agents in human breast cancer cells overexpressing stathmin. We found that targeting stathmin or wee-1 expression with RNA interference can induce microtubule polymerization and promote G2/M progression, respectively, and sensitize stathmin-overexpressing breast cancer cells to paclitaxel and vinblastine. Furthermore, targeting wee-1 led to the phosphorylation of stathmin, which is known to attenuate its activity. Therefore, these data suggest a novel approach to improving the efficacy of certain antimicrotubule agents against breast cancer by regulating the function of stathmin.
Footnotes
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This work was supported by US Public Health Service grants CA78695 and CA72720.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.029702.
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ABBREVIATIONS: cdk1, cyclin dependent kinase 1; RT, reverse transcriptase; qPCR, quantitative polymerase chain reaction; siRNA, small interfering RNA; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide; P:S, ratio of microtubule polymer to soluble tubulin; ΔΔCT, comparative threshold.
- Received August 7, 2006.
- Accepted January 31, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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