| Modulating microtubule stability enhances the cytotoxic response of cancer cells to paclitaxel. | |
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MedLine Citation:
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PMID: 21775522 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The extracellular matrix protein TGFBI enhances the cytotoxic response of cancer cells to paclitaxel by affecting integrin signals that stabilize microtubules. Extending the implications of this knowledge, we tested the more general hypothesis that cancer cell signals which increase microtubule stability before exposure to paclitaxel may increase its ability to stablize microtubules and thereby enhance its cytotoxicity. Toward this end, we performed an siRNA screen to evaluate how genetic depletion affected microtubule stabilization, cell viability and apoptosis. High content microscopical analysis was performed in the absence or presence of paclitaxel. Kinase knockdowns that stabilized microtubules strongly enhanced the effects of paclitaxel treatment. Conversely, kinase knockdowns that enhanced paclitaxel-mediated cytotoxicity sensitized cells to microtubule stabilization by paclitaxel. The siRNA screen identified several genes that have not been linked previously to in microtubule regulation or paclitaxel response. Gene shaving and Bayesian resampling used to classify these genes suggested three pathways of paclitaxel-induced cell death related to apoptosis and microtubule stability, apoptosis alone, or neither process. Our results offer a functional classification of the genetic basis for paclitaxel sensitivity and they support the hypothesis that stablizing microtubules prior to therapy could enhance antitumor responses to paclitaxel treatment. |
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Authors:
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Ahmed Ashour Ahmed; Xiaoyan Wang; Zhen Lu; Juliet Goldsmith; Xiao-Feng Le; Geoffrey Grandjean; Geoffrey Bartholomeusz; Bradley Broom; Robert C Bast |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-7-20 |
Journal Detail:
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Title: Cancer research Volume: - ISSN: 1538-7445 ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-7-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Nuffield Department of Obstetrics and Gynaecology, University of Oxford. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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