title: Mitotic centromere-associated kinesin (MCAK) mediates paclitaxel resistance.
abstract: Paclitaxel has powerful anticancer activity, but some tumors are inherently resistant to the drug, whereas others are initially sensitive but acquire resistance during treatment. To deal with this problem, it will be necessary to understand the mechanisms of drug action and resistance. Recent studies indicate that paclitaxel blocks cell division by inhibiting the detachment of microtubules from centrosomes. Here, we demonstrate that mitotic centromere-associated kinesin (MCAK), a kinesin-related protein that destabilizes microtubules, plays an important role in microtubule detachment. Depletion of MCAK altered mitotic spindle morphology, increased the frequency of lagging chromosomes, and inhibited the proliferation of WT CHO cells, confirming that it is an essential protein for cell division. In contrast, MCAK depletion rescued the proliferation of mutant paclitaxel-dependent cell lines that are unable to divide because of defective spindle function resulting from altered α-tubulin or class III β-tubulin overexpression. In concert with the correction of mitotic defects, loss of MCAK reversed an aberrantly high frequency of microtubule detachment in the mutant cells and increased their sensitivity to paclitaxel. The results indicate that MCAK affects cell sensitivity to mitotic inhibitors by modulating the frequency of microtubule detachment, and they demonstrate that changes in a microtubule-interacting protein can reverse the effects of mutant tubulin expression.
authors: Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77030, USA.
authors: Anutosh
authors: A
authors: Ganguly
authors: Hailing
authors: H
authors: Yang
authors: Mesias
authors: M
authors: Pedroza
authors: Rajat
authors: R
authors: Bhattacharya
authors: Fernando
authors: F
authors: Cabral
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017239:Paclitaxel / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; C490417:mitotic centromere-associated kinesin, hamster; D016547:Kinesins; D017239:Paclitaxel