title: Chemically diverse microtubule stabilizing agents initiate distinct mitotic defects and dysregulated expression of key mitotic kinases.
abstract: Microtubule stabilizers are some of the most successful drugs used in the treatment of adult solid tumors and yet the molecular events responsible for their antimitotic actions are not well defined. The mitotic events initiated by three structurally and biologically diverse microtubule stabilizers; taccalonolide AJ, laulimalide/fijianolide B and paclitaxel were studied. These microtubule stabilizers cause the formation of aberrant, but structurally distinct mitotic spindles leading to the hypothesis that they differentially affect mitotic signaling. Each microtubule stabilizer initiated different patterns of expression of key mitotic signaling proteins. Taccalonolide AJ causes centrosome separation and disjunction failure to a much greater extent than paclitaxel or laulimalide, which is consistent with the distinct defects in expression and activation of Plk1 and Eg5 caused by each stabilizer. Localization studies revealed that TPX2 and Aurora A are associated with each spindle aster formed by each stabilizer. This suggests a common mechanism of aster formation. However, taccalonolide AJ also causes pericentrin accumulation on every spindle aster. The presence of pericentrin at every spindle aster initiated by taccalonolide AJ might facilitate the maintenance and stability of the highly focused asters formed by this stabilizer. Laulimalide and paclitaxel cause completely different patterns of expression and activation of these proteins, as well as phenotypically different spindle phenotypes. Delineating how diverse microtubule stabilizers affect mitotic signaling pathways could identify key proteins involved in modulating sensitivity and resistance to the antimitotic actions of these compounds.
authors: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors: Cristina C
authors: CC
authors: Rohena
authors: Jiangnan
authors: J
authors: Peng
authors: Tyler A
authors: TA
authors: Johnson
authors: Phillip
authors: P
authors: Crews
authors: Susan L
authors: SL
authors: Mooberry
mesh_terms: D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism; D018385:Centrosome / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000201:enzymology; D008938:Mitosis / Q000187:drug effects*; D009687:Nuclear Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects / Q000201:enzymology; D013256:Steroids / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
chemical_list: D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D016547:Kinesins; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013256:Steroids; D050257:Tubulin Modulators; D000097869:Polo-Like Kinase 1; C470243:KIF11 protein, human; C120551:TACC3 protein, human; C122167:TPX2 protein, human; C117305:laulimalide; C570719:taccalonolide AJ
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