Reversal of stathmin-mediated resistance to paclitaxel and vinblastine in human breast carcinoma cells.
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 G(2) 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 G(2)/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.
Alli
Elizabeth
E
The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Department of Pharmacology, New Brunswick, NJ 08901, USA.
Yang
Jin-Ming
JM
Ford
James M
JM
Hait
William N
WN
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050777:Stathmin / Q000378:metabolism*; D014747:Vinblastine / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D050777:Stathmin; D014747:Vinblastine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D017239:Paclitaxel