Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs.
Drugs that target microtubules are thought to inhibit cell division and cell migration by suppressing dynamic instability, a "search and capture" behavior that allows microtubules to probe their environment. Here, we report that subtoxic drug concentrations are sufficient to inhibit plus-end microtubule dynamic instability and cell migration without affecting cell division or microtubule assembly. The higher drug concentrations needed to inhibit cell division act through a novel mechanism that generates microtubule fragments by stimulating microtubule minus-end detachment from their organizing centers. The frequency of microtubule detachment in untreated cells increases at prophase suggesting that it is a regulated cellular process important for spindle assembly and function. We conclude that drugs produce differential dose-dependent effects at microtubule plus and minus-ends to inhibit different microtubule-mediated functions.
Yang
Hailing
H
Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77030, USA.
Ganguly
Anutosh
A
Cabral
Fernando
F
D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D019556:COS Cells / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D018385:Centrosome / Q000378:metabolism; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003703:Demecolcine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
D008869:Microtubule-Associated Proteins; D014404:Tubulin; D050257:Tubulin Modulators; D014747:Vinblastine; D003703:Demecolcine