Abstract 4501: Diverse microtubule stabilizers cause differential expression of mitotic kinases leading to distinct centrosomal and mitotic defects.

Abstract

Abstract Microtubule stabilizers are some of the most useful and successful drugs used to treat adult solid tumors. However, the molecular events responsible for their antimitotic actions are not yet fully understood. In this study we evaluated the mitotic defects and signaling events initiated by three structurally and biologically different microtubule stabilizers; taccalonolide AJ, laulimalide/fijianolide B and paclitaxel. These microtubule stabilizers cause the formation of aberrant, but morphologically distinct mitotic spindles leading to the hypothesis that they initiate distinct mitotic signaling events. Each microtubule stabilizer caused different patterns of expression of key mitotic signaling proteins. Taccalonolide AJ caused centrosome separation failure to a much greater extent than paclitaxel or laulimalide. Taccalonolide AJ is also unique in that it was the only stabilizer to cause centrosome disjunction failure. These observations were consistent with the different 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, which suggests a common mechanism of aster formation. However, taccalonolide AJ was the only stabilizer evaluated that caused pericentrin accumulation on every spindle aster. Pericentrin's localization to every spindle aster could facilitate the maintenance and stability of the highly focused asters formed by taccalonolide AJ. Laulimalide and paclitaxel caused completely different patterns of expression and activation of these proteins, as well as phenotypically different spindle phenotypes. Elucidating how chemically distinct microtubule stabilizers disturb mitotic signaling could identify key proteins involved in controlling sensitivity and resistance to the antimitotic actions of these agents. Citation Format: Cristina C. Rohena, Jiangnan Peng, Tyler A. Johnson, Phillip Crews, Susan L. Mooberry. Diverse microtubule stabilizers cause differential expression of mitotic kinases leading to distinct centrosomal and mitotic defects. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4501. doi:10.1158/1538-7445.AM2013-4501