title: Modulating microtubule stability enhances the cytotoxic response of cancer cells to Paclitaxel.
abstract: 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.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA. rbast@mdanderson.org
authors.forename: Ahmed Ashour
authors.initials: AA
authors.lastname: Ahmed
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.forename: Juliet
authors.initials: J
authors.lastname: Goldsmith
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Le
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Grandjean
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bartholomeusz
authors.forename: Bradley
authors.initials: B
authors.lastname: Broom
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
mesh_terms: D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D003603:Cytotoxins; D034741:RNA, Small Interfering; D050257:Tubulin Modulators; D017239:Paclitaxel