Document Detail


Modulating microtubule stability enhances the cytotoxic response of cancer cells to Paclitaxel.
MedLine Citation:
PMID:  21775522     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 stabilize microtubules and thereby enhance its cytotoxicity. Toward this end, we carried out an siRNA screen to evaluate how genetic depletion affected microtubule stabilization, cell viability, and apoptosis. High content microscopic analysis was carried out 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 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 stabilizing microtubules prior to therapy could enhance antitumor responses to paclitaxel treatment.
Authors:
Ahmed Ashour Ahmed; Xiaoyan Wang; Zhen Lu; Juliet Goldsmith; Xiao-Feng Le; Geoffrey Grandjean; Geoffrey Bartholomeusz; Bradley Broom; Robert C Bast
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-20
Journal Detail:
Title:  Cancer research     Volume:  71     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-01     Completed Date:  2011-10-25     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5806-17     Citation Subset:  IM    
Copyright Information:
©2011 AACR.
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Tumor
Cytotoxins / pharmacology*
Drug Resistance, Neoplasm*
Humans
Microtubules / genetics,  metabolism*
Neoplasms / metabolism*
Paclitaxel / pharmacology*
RNA, Small Interfering / genetics
Tubulin Modulators / pharmacology*
Grant Support
ID/Acronym/Agency:
P50 CA083639/CA/NCI NIH HHS; P50 CA083639/CA/NCI NIH HHS; P50 CA083639-09/CA/NCI NIH HHS; //Cancer Research UK
Chemical
Reg. No./Substance:
0/Cytotoxins; 0/RNA, Small Interfering; 0/Tubulin Modulators; 33069-62-4/Paclitaxel
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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